Analysis of representative mutants for key DNA repair pathways on healthspan in Caenorhabditis elegans.
Analysis of representative mutants for key DNA repair pathways on healthspan in Caenorhabditis elegans.
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DOI：
10.1016/j.mad.2021.111573
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发表时间：
2021-12
影响因子：
5.3
通讯作者：
Gurkar AU
中科院分区：
文献类型：
--
作者：
Marchal L;Hamsanathan S;Karthikappallil R;Han S;Shinglot H;Gurkar AU
虽然DNA损伤与衰老之间的联系已被广泛接受，但不同的DNA修复蛋白在功能性/生理性衰老中的作用尚不清楚。在这里，我们利用秀丽线虫，系统地检测了三个DNA修复基因在关键基因组稳定途径中的作用。我们分析了多种健康指标，包括分子、功能和弹性指标，以定义健康寿命。XPF-1/ERCC-1是一种参与核苷酸切除修复(NER)、同源重组(HR)和链间交联(ICL)修复的蛋白质，其突变显示出功能和应激恢复能力的最高损害，并伴随着寿命的缩短。BRC-1突变体在HR和ICL中具有明确的作用，是短暂的，对急性应激源，特别是氧化应激高度敏感。相比之下，ICL突变体FCD-2不会影响寿命或大多数健康指标。我们的工作还发现，DNA修复突变随着年龄的增长对氧化应激表现出高度的敏感性，这表明这一指标可以作为健康跨度的主要替代指标。总之，这些数据表明，多个DNA修复基因的损伤可能会导致功能性/生理性衰老。以组织特异性方式检测特定DNA修复基因的进一步研究将有助于剖析这些修复系统在生物衰老中的重要性和机制作用。
Although the link between DNA damage and aging is well accepted, the role of different DNA repair proteins on functional/physiological aging is not well-defined. Here, using Caenorhabditis elegans, we systematically examined the effect of three DNA repair genes involved in key genomic stability pathways. We assayed multiple health proxies including molecular, functional and resilience measures to define healthspan. Mutation in XPF-1/ERCC-1, a protein involved in nucleotide excision repair (NER), homologous recombination (HR) and interstrand crosslink (ICL) repair, showed the highest impairment of functional and stress resilience measures along with a shortened lifespan. brc-1 mutants, with a well-defined role in HR and ICL are short-lived and highly sensitive to acute stressors, specifically oxidative stress. In contrast, ICL mutants fcd-2 did not impact lifespan or most healthspan measures. Our efforts also uncover that DNA repair mutants show high sensitivity to oxidative stress with age, suggesting that this measure could act as a primary proxy for healthspan. Together, these data suggest that impairment of multiple DNA repair genes can drive functional/physiological aging. Further studies to examine specific DNA repair genes in a tissue specific manner will help dissect the importance and mechanistic role of these repair systems in biological aging.
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影响因子：
9.8
作者：
Bogliolo, Massimo;Schuster, Beatrice;Surralles, Jordi
通讯作者：
Surralles, Jordi
影响因子：
4.5
作者：
Agostinho A;Meier B;Sonneville R;Jagut M;Woglar A;Blow J;Jantsch V;Gartner A
通讯作者：
Gartner A
影响因子：
64.8
作者：
通讯作者：
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影响因子：
45.3
作者：
Armstrong, Gregory T.;Kawashima, Toana;Oeffinger, Kevin C.
通讯作者：
Oeffinger, Kevin C.
影响因子：
64.5
作者：
BARGMANN, CI;HARTWIEG, E;HORVITZ, HR
通讯作者：
HORVITZ, HR