The human RecQ helicases BLM and RECQL4 cooperate to preserve genome stability

Bacteria and yeast possess one RecQ helicase homolog whereas humans contain five RecQ helicases, all of which are important in preserving genome stability. Three of these, BLM, WRN and RECQL4, are mutated in human diseases manifesting in premature aging and cancer. We are interested in determining t...

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Published in:Nucleic acids research 2012-08, Vol.40 (14), p.6632-6648
Main Authors: Singh, Dharmendra Kumar, Popuri, Venkateswarlu, Kulikowicz, Tomasz, Shevelev, Igor, Ghosh, Avik K, Ramamoorthy, Mahesh, Rossi, Marie L, Janscak, Pavel, Croteau, Deborah L, Bohr, Vilhelm A
Format: Article
Language:English
Subjects:
Cell Line
DNA - metabolism
DNA Damage
Genome Integrity, Repair and
Genomic Instability
Guanine - analogs & derivatives
Guanine - metabolism
HeLa Cells
Humans
Protein Interaction Domains and Motifs
RecQ Helicases - chemistry
RecQ Helicases - metabolism
S Phase
Sister Chromatid Exchange
Thymine - analogs & derivatives
Thymine - metabolism
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Summary:Bacteria and yeast possess one RecQ helicase homolog whereas humans contain five RecQ helicases, all of which are important in preserving genome stability. Three of these, BLM, WRN and RECQL4, are mutated in human diseases manifesting in premature aging and cancer. We are interested in determining to which extent these RecQ helicases function cooperatively. Here, we report a novel physical and functional interaction between BLM and RECQL4. Both BLM and RECQL4 interact in vivo and in vitro. We have mapped the BLM interacting site to the N-terminus of RECQL4, comprising amino acids 361-478, and the region of BLM encompassing amino acids 1-902 interacts with RECQL4. RECQL4 specifically stimulates BLM helicase activity on DNA fork substrates in vitro. The in vivo interaction between RECQL4 and BLM is enhanced during the S-phase of the cell cycle, and after treatment with ionizing radiation. The retention of RECQL4 at DNA double-strand breaks is shortened in BLM-deficient cells. Further, depletion of RECQL4 in BLM-deficient cells leads to reduced proliferative capacity and an increased frequency of sister chromatid exchanges. Together, our results suggest that BLM and RECQL4 have coordinated activities that promote genome stability.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gks349