TY - JOUR
T1 - Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair
AU - Lu, Huiming
AU - Shamanna, Raghavendra A.
AU - de Freitas, Jessica K.
AU - Okur, Mustafa
AU - Khadka, Prabhat
AU - Kulikowicz, Tomasz
AU - Holland, Priscella P.
AU - Tian, Jane
AU - Croteau, Deborah L.
AU - Davis, Anthony J.
AU - Bohr, Vilhelm A.
N1 - Funding Information:
We thank Dr. Xiaofan Wang, Dr. Jeremy Stark, Dr. Gaëlle Legube, and Dr. Petr Cejka for DR-GFP U2OS, EJ5 U2OS, AID-DIVA U2OS, and MRN proteins. We also thank Alfred May and Dr. Janapriya Saha for IR operation, and Drs. Jong-Hyuk Lee and Tyler Demarest for their critical comments. This research was supported mainly by the Intramural Research Program of the NIH, National Institute on Aging (V.A.B.), and also by grants from the National Institutes of Health CA092584 and CA162804 (A.J.D.).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-02146-3
DO - 10.1038/s41467-017-02146-3
M3 - Article
C2 - 29229926
AN - SCOPUS:85047899411
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2039
ER -