Changes in DNA repair compartments and cohesin loss promote DNA damage accumulation in aged oocytes.

IF 8.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Current Biology Pub Date : 2024-11-18 Epub Date: 2024-10-21 DOI:10.1016/j.cub.2024.09.040
Ninadini Sharma, Giovanni Coticchio, Andrea Borini, Kikuë Tachibana, Kim A Nasmyth, Melina Schuh
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Abstract

Oocyte loss, a natural process that accelerates as women approach their mid-30s, poses a significant challenge to female reproduction. Recent studies have identified DNA damage as a primary contributor to oocyte loss, but the mechanisms underlying DNA damage accumulation remain unclear. Here, we show that aged oocytes have a lower DNA repair capacity and reduced mobility of DNA damage sites compared to young oocytes. Incomplete DNA repair in aged oocytes results in defective chromosome integrity and partitioning, thereby compromising oocyte quality. We found that DNA repair proteins are arranged in spatially distinct DNA repair compartments that form during the late stages of oocyte growth, accompanied by changes in the activity of DNA repair pathways. We demonstrate alterations in these compartments with age, including substantial changes in the levels of key DNA repair proteins and a shift toward error-prone DNA repair pathways. In addition, we show that reduced cohesin levels make aged oocytes more vulnerable to persistent DNA damage and cause changes in DNA repair compartments. Our study links DNA damage accumulation in aged oocytes, a leading cause of oocyte loss, to cohesin deterioration and changes in the organization, abundance, and response of DNA repair machinery.

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DNA 修复区的变化和凝聚素的缺失会促进衰老卵母细胞中 DNA 损伤的积累。
卵母细胞丢失是一个自然过程,在女性接近 30 岁时会加速,这给女性生殖带来了巨大挑战。最近的研究发现,DNA损伤是导致卵母细胞丢失的主要因素,但DNA损伤累积的机制仍不清楚。在这里,我们发现,与年轻卵母细胞相比,老年卵母细胞的DNA修复能力较低,DNA损伤位点的移动性也降低了。衰老卵母细胞中不完全的DNA修复会导致染色体完整性和分区缺陷,从而影响卵母细胞的质量。我们发现,DNA 修复蛋白排列在空间上不同的 DNA 修复区中,这些区在卵母细胞生长后期形成,并伴随着 DNA 修复途径活性的变化。我们证明了这些区室随着年龄的增长而发生的变化,包括关键 DNA 修复蛋白水平的显著变化以及向易出错 DNA 修复途径的转变。此外,我们还发现,凝聚素水平的降低使老年卵母细胞更容易受到持续的DNA损伤,并导致DNA修复区发生变化。我们的研究将衰老卵母细胞中的DNA损伤积累(卵母细胞丢失的主要原因)与凝聚素退化以及DNA修复机制的组织、丰度和反应的变化联系起来。
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来源期刊
Current Biology
Current Biology 生物-生化与分子生物学
CiteScore
11.80
自引率
2.20%
发文量
869
审稿时长
46 days
期刊介绍: Current Biology is a comprehensive journal that showcases original research in various disciplines of biology. It provides a platform for scientists to disseminate their groundbreaking findings and promotes interdisciplinary communication. The journal publishes articles of general interest, encompassing diverse fields of biology. Moreover, it offers accessible editorial pieces that are specifically designed to enlighten non-specialist readers.
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