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2014 ; 111
(49
): 17456-61
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UbcH7 regulates 53BP1 stability and DSB repair
#MMPMID25422456
Han X
; Zhang L
; Chung J
; Mayca Pozo F
; Tran A
; Seachrist DD
; Jacobberger JW
; Keri RA
; Gilmore H
; Zhang Y
Proc Natl Acad Sci U S A
2014[Dec]; 111
(49
): 17456-61
PMID25422456
show ga
DNA double-strand break (DSB) repair is not only key to genome stability but is
also an important anticancer target. Through an shRNA library-based screening, we
identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a
ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the
steady-state and replicative stress-induced ubiquitination and
proteasome-dependent degradation of the tumor suppressor p53-binding protein 1
(53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the
replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes
53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted
cells display increased nonhomologous end-joining and reduced homologous
recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to
DNA damage likely because they mainly used the error-prone nonhomologous
end-joining pathway to repair DSBs. Our studies reveal a novel layer of
regulation of the DSB repair choice and propose an innovative approach to enhance
the effect of radiotherapy or chemotherapy through stabilizing 53BP1.
|*DNA Breaks, Double-Stranded
[MESH]
|*DNA Repair
[MESH]
|*Gene Expression Regulation, Neoplastic
[MESH]
|Camptothecin/chemistry
[MESH]
|Cell Line, Tumor
[MESH]
|Cell Survival
[MESH]
|DNA Damage
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins/*metabolism
[MESH]
free
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