The consequences of differential origin licensing dynamics in distinct chromatin environments.
The consequences of differential origin licensing dynamics in distinct chromatin environments.
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DOI：
10.1093/nar/gkac003
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发表时间：
2022-09-23
影响因子：
14.9
通讯作者：
Cook, Jeanette Gowen
中科院分区：
文献类型：
--
作者：
Mei, Liu;Kedziora, Katarzyna M.;Song, Eun-Ah;Purvis, Jeremy E.;Cook, Jeanette Gowen
真核染色体包含不同的可及性区域，但DNA复制因子必须访问所有区域。第一个复制步骤是在G1细胞周期阶段加载MCM复合物以许可复制起点。目前尚不清楚哺乳动物MCM复合物如何充分分布到可接近的常染色质区域和不易接近的异染色质区域。为了解决这个问题，我们结合了延时活细胞成像与单个人类细胞的免疫荧光成像，以量化MCM加载在整个G1的常染色质和异染色质中的相对速率。我们在这里报告说，MCM加载在常染色质是快于异染色质在早期G1，但令人惊讶的是，异染色质加载加速相对于常染色质加载在中期和晚期G1。这种差异加速允许两种染色质类型以相似浓度的负载MCM开始S期。不同的加载动力学需要ORCA依赖的差异，在起源识别复杂的分布。异染色质许可动力学的一个结果是，细胞经历了一个截短的G1期从过早的细胞周期蛋白E表达进入S期与许可不足的异染色质，和DNA损伤积累优先在异染色质在随后的S/G2期。因此，G1长度对于足够的MCM加载是至关重要的，特别是在异染色质中，以确保完整的基因组复制和维持基因组稳定性。
Eukaryotic chromosomes contain regions of varying accessibility, yet DNA replication factors must access all regions. The first replication step is loading MCM complexes to license replication origins during the G1 cell cycle phase. It is not yet known how mammalian MCM complexes are adequately distributed to both accessible euchromatin regions and less accessible heterochromatin regions. To address this question, we combined time-lapse live-cell imaging with immunofluorescence imaging of single human cells to quantify the relative rates of MCM loading in euchromatin and heterochromatin throughout G1. We report here that MCM loading in euchromatin is faster than that in heterochromatin in early G1, but surprisingly, heterochromatin loading accelerates relative to euchromatin loading in middle and late G1. This differential acceleration allows both chromatin types to begin S phase with similar concentrations of loaded MCM. The different loading dynamics require ORCA-dependent differences in origin recognition complex distribution. A consequence of heterochromatin licensing dynamics is that cells experiencing a truncated G1 phase from premature cyclin E expression enter S phase with underlicensed heterochromatin, and DNA damage accumulates preferentially in heterochromatin in the subsequent S/G2 phase. Thus, G1 length is critical for sufficient MCM loading, particularly in heterochromatin, to ensure complete genome duplication and to maintain genome stability.
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影响因子：
7.7
作者：
Giri, Sumanprava;Aggarwal, Vasudha;Prasanth, Supriya G.
通讯作者：
Prasanth, Supriya G.
影响因子：
16
作者：
Foti R;Gnan S;Cornacchia D;Dileep V;Bulut-Karslioglu A;Diehl S;Buness A;Klein FA;Huber W;Johnstone E;Loos R;Bertone P;Gilbert DM;Manke T;Jenuwein T;Buonomo SC
通讯作者：
Buonomo SC
影响因子：
4
作者：
Giri, Sumanprava;Chakraborty, Arindam;Prasanth, Supriya G.
通讯作者：
Prasanth, Supriya G.
影响因子：
7
作者：
Cayrou, Christelle;Coulombe, Philippe;Mechali, Marcel
通讯作者：
Mechali, Marcel
影响因子：
10.5
作者：
Eaton, Matthew L.;Galani, Kyriaki;MacAlpine, David M.
通讯作者：
MacAlpine, David M.