Homologous recombination-dependent repair of telomeric DSBs in proliferating human cells

Pingsu Mao, Jingfan Liu, Zepeng Zhang, Hong Zhang, Haiying Liu, Song Gao, Yikang S. Rong and Yong Zhao ()
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Pingsu Mao: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University
Jingfan Liu: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University
Zepeng Zhang: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University
Hong Zhang: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University
Haiying Liu: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University
Song Gao: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
Yikang S. Rong: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University
Yong Zhao: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Telomeres prevent chromosome ends from being recognized as double-stranded breaks (DSBs). Meanwhile, G/C-rich repetitive telomeric DNA is susceptible to attack by DNA-damaging agents. How cells balance the need to protect DNA ends and the need to repair DNA lesions in telomeres is unknown. Here we show that telomeric DSBs are efficiently repaired in proliferating cells, but are irreparable in stress-induced and replicatively senescent cells. Using the CRISPR-Cas9 technique, we specifically induce DSBs at telomeric or subtelomeric regions. We find that DSB repair (DSBR) at subtelomeres occurs in an error-prone manner resulting in small deletions, suggestive of NHEJ. However, DSBR in telomeres involves ‘telomere-clustering’, 3′-protruding C-rich telomeric ssDNA, and HR between sister-chromatid or interchromosomal telomeres. DSBR in telomeres is suppressed by deletion or inhibition of Rad51. These findings reveal proliferation-dependent DSBR in telomeres and suggest that telomeric HR, which is normally constitutively suppressed, is activated in the context of DSBR.

Date: 2016
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DOI: 10.1038/ncomms12154

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