PCNA antagonizes cohesin-dependent roles in genomic stability.
PCNA antagonizes cohesin-dependent roles in genomic stability.
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DOI：
10.1371/journal.pone.0235103
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Skibbens RV
中科院分区：
文献类型：
--
作者：
Zuilkoski CM;Skibbens RV
PCNA滑动钳结合因子，通过这些因子，组蛋白沉积、染色质重塑和DNA修复与DNA复制偶联。PCNA还直接结合Eco 1/Ctf 7乙酰转移酶，其反过来激活粘附素并在新生姐妹染色单体之间建立粘附。虽然增加招聘，从而解释了机制，通过提高水平的染色质结合PCNA救援eco 1突变细胞生长，通过PCNA而不是cohesin突变细胞生长的机制仍然未知。可能包括，高水平的长寿命染色质结合的PCNA减少粘附蛋白沉积到DNA或粘附蛋白乙酰化。相反，我们的研究结果表明，PCNA增加染色质结合的cohesin和cohesin乙酰化的水平。除了姐妹染色单体的凝聚力，PCNA也在基因组稳定性中起着关键作用，例如高水平的染色质结合的PCNA提高遗传毒性敏感性和重组率。在一个相对温和的增加染色质结合的PCNA，然而，叉稳定性和进展出现正常的野生型细胞。我们的研究结果表明，即使是适度增加的PCNA确实敏感的cohesin突变细胞的DNA损伤剂，并在一个过程中，涉及DNA损伤反应激酶Mec 1（ATR），但不是Tel 1（ATM）。这些和其他研究结果表明，PCNA的错误调节导致基因组的不稳定性，通常是解决的粘附。染色质结合的PCNA水平升高可能因此有助于靶向与癌症相关的粘附性病变细胞。
PCNA sliding clamp binds factors through which histone deposition, chromatin remodeling, and DNA repair are coupled to DNA replication. PCNA also directly binds Eco1/Ctf7 acetyltransferase, which in turn activates cohesins and establishes cohesion between nascent sister chromatids. While increased recruitment thus explains the mechanism through which elevated levels of chromatin-bound PCNA rescue eco1 mutant cell growth, the mechanism through which PCNA instead worsens cohesin mutant cell growth remains unknown. Possibilities include that elevated levels of long-lived chromatin-bound PCNA reduce either cohesin deposition onto DNA or cohesin acetylation. Instead, our results reveal that PCNA increases the levels of both chromatin-bound cohesin and cohesin acetylation. Beyond sister chromatid cohesion, PCNA also plays a critical role in genomic stability such that high levels of chromatin-bound PCNA elevate genotoxic sensitivities and recombination rates. At a relatively modest increase of chromatin-bound PCNA, however, fork stability and progression appear normal in wildtype cells. Our results reveal that even a moderate increase of PCNA indeed sensitizes cohesin mutant cells to DNA damaging agents and in a process that involves the DNA damage response kinase Mec1(ATR), but not Tel1(ATM). These and other findings suggest that PCNA mis-regulation results in genome instabilities that normally are resolved by cohesin. Elevating levels of chromatin-bound PCNA may thus help target cohesinopathic cells linked that are linked to cancer.