The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

被引:10
|
作者
Muraki, Keiko [1 ,2 ]
Murnane, John P. [2 ]
机构
[1] Osaka Univ, Inst Prot Res, 3-2 Yamadaoka, Suita, Osaka 5650871, Japan
[2] Univ Calif San Francisco, Dept Radiat Oncol, 2340 Sutter St, San Francisco, CA 94143 USA
关键词
C-NHEJ; A-NHEJ; processing; rearrangements; subtelomere; MAINTAINS GENOMIC STABILITY; CLASS SWITCH RECOMBINATION; REPAIR PATHWAY CHOICE; HOMOLOGOUS RECOMBINATION; MAMMALIAN TELOMERES; TUMOR SUPPRESSION; END RESECTION; HUMAN-CELLS; CHROMOSOME INSTABILITY; KAP-1; PHOSPHORYLATION;
D O I
10.1266/ggs.17-00014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.
引用
收藏
页码:135 / 152
页数:18
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