Summary: HRDC domain

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Wikipedia: RecQ helicase
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This is the Wikipedia entry entitled "RecQ helicase". More...

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RecQ helicase

Bloom syndrome
Identifiers
Symbol	BLM
Entrez	641
HUGO	1058
OMIM	604610
RefSeq	NM_000057
UniProt	P54132
Other data
Locus	Chr. 15 [1]

RecQ protein-like 4
Identifiers
Symbol	RECQL4
Entrez	9401
HUGO	9949
OMIM	603780
RefSeq	NM_004260
UniProt	O94761
Other data
Locus	Chr. 8 q24.3

RecQ protein-like 5
Identifiers
Symbol	RECQL5
Entrez	9400
HUGO	9950
OMIM	603781
RefSeq	NM_004259
UniProt	O94762
Other data
Locus	Chr. 17 q25

RMI1, RecQ mediated genome instability 1
Identifiers
Symbol	RMI1
Alt. symbols	C9orf76
Entrez	80010
HUGO	25764
OMIM	610404
RefSeq	NM_024945
UniProt	Q9H9A7
Other data
Locus	Chr. 9 q22.1

Werner syndrome
Identifiers
Symbol	WRN
Entrez	7486
HUGO	12791
OMIM	604611
RefSeq	NM_000553
UniProt	Q14191
Other data
Locus	Chr. 8 p

RecQ helicase is a family of helicase enzymes that has been shown to be important in genome maintenance.^[1]^[2]^[3] They function through catalyzing the reaction ATP + H₂O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H₂O → NDP + P to drive the unwinding of either DNA or RNA.

[edit] Function

In prokaryotes RecQ is necessary for plasmid recombination and DNA repair from UV-light, free radicals, and alkylating agents. This protein can also reverse damage from replication errors. In eukaryotes, replication does not proceed normally in the absence of RecQ proteins, which also function in aging, silencing, recombination and DNA repair.

[edit] Structure

RecQ family members share three regions of conserved protein sequence referred to as the:

N-terminal – Helicase
middle – RecQ-conserved (RecQ-Ct) and
C-terminal – Helicase-and-RNase-D C-terminal (HRDC) domains.

The removal of the N-terminal residues (Helicase and, RecQ-Ct domains) impairs both helicase and ATPase activity but has no effect on the binding ability of RecQ implying that the N-terminus functions as the catalytic end. Truncations of the C-terminus (HRDC domain) compromise the binding ability of RecQ but not the catalytic function. The importance of RecQ in cellular functions is exemplified by human diseases, which all lead to genomic instability and a predisposition to cancer.

[edit] Clinical significance

There are at least five human RecQ genes; and mutations in any of the three human RecQ genes are implicated in heritable human diseases: WRN gene in Werner syndrome (WS), BLM gene in Bloom syndrome (BS), and RECQ4 in Rothmund-Thomson syndrome.^[4] These syndromes are characterized by premature ageing, graying and loss of hair, cancer, type II diabetes, osteoporosis, and atherosclerosis, all of which are diseases that are common at old age. These diseases are associated with high incidence of chromosomal abnormalities, including chromosome breaks, complex rearrangements, deletions and translocations, site specific mutations, and in particular sister chromatid exchanges (more common in BS) that are believed to be caused by a high level of somatic recombination.

[edit] Mechanism

The proper function of RecQ helicases requires the specific interaction with topoisomerase III (Top 3). Top 3 changes the topological status of DNA by binding and cleaving single stranded DNA and passing either a single stranded or a double stranded DNA segment through the transient break and finally religating the break. The interaction of RecQ helicase with topoisomerase III at the N-terminal region is involved in the suppression of spontaneous and damage induced recombination and the absence of this interaction results in a lethal or very severe phenotype. The emerging picture clearly is that RecQ helicases in concert with Top 3 are involved in maintaining genomic stability and integrity by controlling recombination events, and repairing DNA damage in the G2-phase of the cell cycle. The importance of RecQ for genomic integrity is exemplified by the diseases that arise as a consequence of mutations or malfunctions in RecQ helicases; thus it is crucial that RecQ is present and functional to ensure proper human growth and development.

[edit] References

^ Cobb JA, Bjergbaek L, Gasser SM (October 2002). "RecQ helicases: at the heart of genetic stability". FEBS Lett. 529 (1): 43–8. doi:10.1016/S0014-5793(02)03269-6. PMID 12354611.
^ Kaneko H, Fukao T, Kondo N (2004). "The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining". Adv. Biophys. 38: 45–64. doi:10.1016/S0065-227X(04)80061-3. PMID 15493327.
^ Ouyang KJ, Woo LL, Ellis NA (2008). "Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases". Mech. Ageing Dev. 129 (7-8): 425–40. doi:10.1016/j.mad.2008.03.003. PMID 18430459.
^ Hanada K, Hickson ID (September 2007). "Molecular genetics of RecQ helicase disorders". Cell. Mol. Life Sci. 64 (17): 2306–22. doi:10.1007/s00018-007-7121-z. PMID 17571213.

[edit] Further reading

Bernstein DA, Keck JL (June 2003). "Domain mapping of Escherichia coli RecQ defines the roles of conserved N- and C-terminal regions in the RecQ family". Nucleic Acids Res. 31 (11): 2778–85. doi:10.1093/nar/gkg376. PMC 156711. PMID 12771204. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=156711.
Skouboe C, Bjergbaek L, Andersen AH (2005). "Genome instability as a cause of ageing and cancer: Implications of RecQ helicases". Signal Transduction 5 (3): 142–151. doi:10.1002/sita.200400052.
Laursen LV, Bjergbaek L, Murray JM, Andersen AH (2003). "RecQ helicases and topoisomerase III in cancer and aging". Biogerontology 4 (5): 275–87. doi:10.1023/A:1026218513772. PMID 14618025.

[edit] External links

RecQ Helicases, introduction at UNC's Selsky Lab.
BLM gene encodes a RecQ Helicase, description of the gene

Hydrolases: acid anhydride hydrolases (EC 3.6)

3.6.1

Pyrophosphatase (Inorganic, Thiamine) · Apyrase · Thiamine-triphosphatase

3.6.2

Adenylylsulfatase · Phosphoadenylylsulfatase

3.6.3-4: ATPase

3.6.3

Cu++ (3.6.3.4)	Menkes/ATP7A · Wilson/ATP7B

Ca+ (3.6.3.8)	SERCA (ATP2A1, ATP2A2, ATP2A3) · Plasma membrane (ATP2B1, ATP2B2, ATP2B3, ATP2B4) · SPCA (ATP2C1, ATP2C2)

Na+/K+ (3.6.3.9)	ATP1A1 · ATP1A2 · ATP1A3 · ATP1A4 · ATP1B1 · ATP1B2 · ATP1B3 · ATP1B4

H+/K+ (3.6.3.10)	ATP4A

Other P-type ATPase	ATP8B1 · ATP10A · ATP11B · ATP12A · ATP13A2 · ATP13A3 ·

3.6.4

Dynein · Kinesin · Myosin · Katanin

3.6.5: GTPase

3.6.5.1: Heterotrimeric G protein	G_αs · G_αi (GNAI1, GNAI2, GNAI3) · G_αq/11 (GNAQ, GNA11) · G_α12/13 (GNA12, GNA13) · Transducin (GNAT1, GNAT2)

3.6.5.2: Small GTPase > Ras superfamily	Rho family of GTPases: Cdc42 (CDC42, TC10, TCL) • RhoUV (RhoU, RhoV) • Rac (Rac1, 2, 3, RhoG) • RhoBTB (1, 2) • RhoH • Rho (A, B, C) • Rnd (1, 2, 3) • RhoDF (RhoF, RhoD) other: Ras (HRAS, KRAS, NRAS) · Rab (RAB23, RAB27) · Arf (ARF6, SAR1B, ARL13B, ARL6) · Ran · Rheb · Rap

3.6.5.3: Protein-synthesizing GTPase	Prokaryotic (IF-2, EF-Tu, EF-G) · Eukaryotic

3.6.5.5-6: Polymerization motors	Dynamin · Tubulin

B
enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
2.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
2.7.10
2.7.11-12
3.1
- 2
- 3
- 4
- 5
- 6
- 7
3.1.3.48
3.4.21
- 22
- 23
- 24
4.1
- 2
- 3
- 4
- 5
- 6
5.1
- 2
- 3
- 4
- 99
6.1-3
- 4
- 5-6

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

HRDC domain

The HRDC (Helicase and RNase D C-terminal) domain has a putative role in nucleic acid binding. Mutations in the HRDC domain cause human disease. It is interesting to note that the RecQ helicase in Deinococcus radiodurans has three tandem HRDC domains [4].

Literature references

Morozov V, Mushegian AR, Koonin EV, Bork P; , Trends Biochem Sci 1997;22:417-418.: A putative nucleic acid-binding domain in Bloom's and Werner's syndrome helicases PUBMED:9397680
Wu L, Chan KL, Ralf C, Bernstein DA, Garcia PL, Bohr VA, Vindigni A, Janscak P, Keck JL, Hickson ID; , EMBO J. 2005;24:2679-2687.: The HRDC domain of BLM is required for the dissolution of double Holliday junctions. PUBMED:15990871
Liu Z, Macias MJ, Bottomley MJ, Stier G, Linge JP, Nilges M, Bork P, Sattler M; , Structure. 1999;7:1557-1566.: The three-dimensional structure of the HRDC domain and implications for the Werner and Bloom syndrome proteins. PUBMED:10647186
Huang L, Hua X, Lu H, Gao G, Tian B, Shen B, Hua Y; , DNA Repair (Amst). 2006; [Epub ahead of print]: Three tandem HRDC domains have synergistic effect on the RecQ functions in Deinococcus radiodurans. PUBMED:17085080

Clan

This family is a member of clan HRDC-like (CL0426), which has a total of 3 members.

External database links

MIM:	210900 277700
PANDIT:	PF00570
Pseudofam:	PF00570
SCOP:	1d8b
SYSTERS:	HRDC

This tab holds annotation information from the InterPro database.

InterPro entry IPR002121

The HRDC (Helicase and RNase D C-terminal) domain has a putative role in nucleic acid binding. Mutations in the HRDC domain associated with the human BLM gene result in Bloom Syndrome (BS), an autosomal recessive disorder characterised by proportionate pre- and postnatal growth deficiency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin; predisposition to malignancy; and chromosomal instability [PUBMED:9397680].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Cellular component	intracellular (GO:0005622)
Molecular function	nucleic acid binding (GO:0003676)

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan HRDC-like (CL0426), which contains the following 3 members:

Helicase_Sgs1 HRDC RNA_pol_Rpb4

Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (148) Full (4150) NCBI (3568) Metagenomics (961)
Viewer:

Formatting options

Alignment:	Seed (148) Full (4150)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (148) Full (4150) NCBI (3568) Metagenomics (961)
Full length sequences	Full-sequences (4150)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Medline:98060076

Previous IDs:

none

Type:

Domain

Author:

Bateman A

Number in seed:

148

Number in full:

4150

Average length of the domain:

67.30 aa

Average identity of full alignment:

27 %

Average coverage of the sequence by the domain:

11.11 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 15929002 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.4	20.4
Trusted cut-off	20.4	20.4
Noise cut-off	20.3	20.3

Model length:

68

Family (HMM) version:

18

Download:

download the raw HMM for this family

Species distribution

Sunburst
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Colour assignments

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab if you need to select sub-trees and view sequence alignments. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, it's distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
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Interactions

There are 2 interactions for this family. More...

DNA_pol_A_exo1 HRDC

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HRDC domain has been found. There are 13 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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Family: HRDC (PF00570)

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