Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair.

Abstract	Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. After phosphorylation, RECQL4 is ubiquitinated by the DDB1-CUL4A E3 ubiquitin ligase, which facilitates its accumulation at DSBs. Phosphorylation of RECQL4 stimulates its helicase activity, promotes DNA end resection, increases HR and cell survival after ionizing radiation, and prevents cellular senescence. Collectively, we propose that RECQL4 modulates the pathway choice of NHEJ and HR in a cell cycle-dependent manner.
Authors	Huiming Lu, Raghavendra A Shamanna, Jessica K de Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P Holland, Jane Tian, Deborah L Croteau, Anthony J Davis, Vilhelm A Bohr
Journal	Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 2039 (12 11 2017) ISSN: 2041-1723 [Electronic] England
PMID	29229926 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References	CUL4A protein, human Cullin Proteins Cyclin-Dependent Kinases RECQL4 protein, human RecQ Helicases Ku Autoantigen
Topics	Cell Cycle Cell Line, Tumor Cullin Proteins (genetics, metabolism) Cyclin-Dependent Kinases (genetics, metabolism) DNA Breaks, Double-Stranded DNA End-Joining Repair HEK293 Cells Humans Ku Autoantigen (genetics, metabolism) Phosphorylation Protein Binding RNA Interference RecQ Helicases (genetics, metabolism) Recombinational DNA Repair Ubiquitination

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