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

Huiming Lu, Raghavendra A. Shamanna, Jessica K. Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P. Holland, Jane Tian, Deborah L. Croteau, Anthony J. Davis and Vilhelm A. Bohr ()
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Huiming Lu: National Institute on Aging, National Institutes of Health
Raghavendra A. Shamanna: National Institute on Aging, National Institutes of Health
Jessica K. Freitas: National Institute on Aging, National Institutes of Health
Mustafa Okur: National Institute on Aging, National Institutes of Health
Prabhat Khadka: National Institute on Aging, National Institutes of Health
Tomasz Kulikowicz: National Institute on Aging, National Institutes of Health
Priscella P. Holland: National Institute on Aging, National Institutes of Health
Jane Tian: National Institute on Aging, National Institutes of Health
Deborah L. Croteau: National Institute on Aging, National Institutes of Health
Anthony J. Davis: Department of Radiation Oncology, UT Southwestern Medical Center
Vilhelm A. Bohr: National Institute on Aging, National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02146-3

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