RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks.
The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 5' end resection in vivo. RECQL4 physically interacts with MRE11-RAD50-NBS1 (MRN), which senses DSBs and initiates DNA end resection with CtIP. The MRE11 exonuclease regulates the retention of RECQL4 at laser-induced DSBs. RECQL4 also directly interacts with CtIP via its N-terminal domain and promotes CtIP recruitment to the MRN complex at DSBs. Moreover, inactivation of RECQL4's helicase activity impairs DNA end processing and HR-dependent DSBR without affecting its interaction with MRE11 and CtIP, suggesting an important role for RECQL4's unwinding activity in the process. Thus, we report that RECQL4 is an important participant in HR-dependent DSBR.
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Huiming
H
Lu
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Raghavendra A
RA
Shamanna
Center for Healthy Aging and Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
Guido
G
Keijzers
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Roopesh
R
Anand
Center for Healthy Aging and Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
Lene Juel
LJ
Rasmussen
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Petr
P
Cejka
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Deborah L
DL
Croteau
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Center for Healthy Aging and Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: vbohr@nih.gov.
Vilhelm A
VA
Bohr
D002352:Carrier Proteins; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000378:metabolism; D006801:Humans; D000076228:MRE11 Homologue Protein / Q000378:metabolism; D009687:Nuclear Proteins; D053484:RecQ Helicases / Q000378:metabolism*; D059767:Recombinational DNA Repair; D051716:Replication Protein A / Q000378:metabolism; D012097:Repressor Proteins
C486563:BCL11A protein, human; D002352:Carrier Proteins; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D051716:Replication Protein A; D012097:Repressor Proteins; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D000076228:MRE11 Homologue Protein; C097151:Bloom syndrome protein; C506731:RECQL4 protein, human; D053484:RecQ Helicases; D045643:DNA Repair Enzymes
DNA repair; DNA resection; RECQL4; RecQ-like helicase; Rothmund-Thomson syndrome; homologous recombination