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

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Number of pages1
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 11 2017

Fingerprint

phosphorylation
Phosphorylation
Double-Stranded DNA Breaks
Ubiquitination
Homologous Recombination
Joining
strands
Cell Cycle
Repair
deoxyribonucleic acid
Cells
cycles
DNA
Rothmund-Thomson Syndrome
Ubiquitin-Protein Ligases
Cyclin-Dependent Kinases
genome
Cell Aging
G2 Phase
Ionizing radiation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. / Lu, Huiming; Shamanna, Raghavendra A.; de Freitas, Jessica K.; Okur, Mustafa; Khadka, Prabhat; Kulikowicz, Tomasz; Holland, Priscella P.; Tian, Jane; Croteau, Deborah L.; Davis, Anthony J.; Bohr, Vilhelm A.

In: Nature Communications, Vol. 8, No. 1, 11.12.2017.

Research output: Contribution to journalArticle

Lu, H, Shamanna, RA, de Freitas, JK, Okur, M, Khadka, P, Kulikowicz, T, Holland, PP, Tian, J, Croteau, DL, Davis, AJ & Bohr, VA 2017, 'Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair', Nature Communications, vol. 8, no. 1. https://doi.org/10.1038/s41467-017-02146-3
Lu, Huiming ; Shamanna, Raghavendra A. ; de Freitas, Jessica K. ; Okur, Mustafa ; Khadka, Prabhat ; Kulikowicz, Tomasz ; Holland, Priscella P. ; Tian, Jane ; Croteau, Deborah L. ; Davis, Anthony J. ; Bohr, Vilhelm A. / Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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