小柯机器人

德国科隆大学Björn Schumacher等研究人员合作揭示组蛋白介导的修复限制对父本DNA损伤的遗传作用。该项研究成果于2022年12月21日在线发表在《自然》杂志上。

研究人员表明，在性别分离的线虫菌株中，父本而非母本的电离辐射暴露会导致跨代的胚胎死亡。受辐射雄性的后代显示出各种基因组不稳定的表征，包括DNA片段化、染色体重排和非整倍体。父本的DNA双链断裂被母本提供的易错聚合酶theta介导的末端连接所修复。从机制上讲，结果表明，人类组蛋白H1.0的同源物HIS-24或异染色质蛋白HPL-1的耗竭可以显著扭转转基因胚胎的致死性。去除HIS-24或HPL-1可以减少组蛋白3第9位赖氨酸的二甲基化，使电离辐射处理过的P0雄性F1代生殖系中的同源重组修复无误，从而提高F2代的生存能力。这项工作建立了父本辐射暴露对后代健康的遗传后果的机制基础，这与人类的先天性疾病和癌症相关。

据悉，父本的电离辐射暴露如何影响后代的遗传和疾病风险一直是辐射生物学中的一个长期问题。在人类中，近80%的传播性突变产生于父系生殖系，但电离辐射暴露的跨代影响仍有争议，其机制也不清楚。

附：英文原文

Title: Inheritance of paternal DNA damage by histone-mediated repair restriction

Author: Wang, Siyao, Meyer, David H., Schumacher, Bjrn

Issue&Volume: 2022-12-21

Abstract: How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegans strains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. Paternal DNA double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1 generation from ionizing radiation-treated P0 males, consequently improving the viability of the F2 generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.

DOI: 10.1038/s41586-022-05544-w

Source: https://www.nature.com/articles/s41586-022-05544-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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