Rall-Scharpf Melanie, Schlotter Dominik, Koch Philipp, Szafranski Karol, Groth Marco, Sahm Arne, Biber Stephanie, Castaño Bryan A, Heitmeir Benedikt, Zengerling Friedemann, Deniz Miriam, Dallmeier Dhayana, Braig Stefanie, Bonig Halvard, Milyavsky Michael, Pospiech Helmut, Wiesmüller Lisa
Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany.
Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany.
Nucleic Acids Res. 2025 Jun 6;53(11). doi: 10.1093/nar/gkaf498.
The varying incidence of aging-related diseases and the gender gap in life expectancy suggest differences in the aging process between the sexes. Yet, little is known about sex-specific differences in genomic instability, a key factor in aging. Here, we analyzed DNA damage responses (DDRs) in cycling peripheral blood lymphocytes (PBL) and hematopoietic stem and progenitor cells (HSPC) from female and male donors of different age, focusing on replication stress. Transcriptomics revealed striking sex-dependent expression changes in DDR pathways during aging. Particularly, various DDR components, involved in DNA repair and replication fork remodeling, were upregulated with age in men. In older women, functional analysis indicated reduced activity of the Fanconi anemia pathway. Analyses of replication dynamics, PCNA ubiquitination, translesion synthesis (TLS)-polymerase signals, and sensitivities to TLS-polymerase inhibitors indicate a shift from fork remodeling to fast TLS inducing nonclassical replication stress. While replication dynamics were unaltered and replication stress rather reduced, PBL from older men were highly dependent on PARP activity. In conclusion, our findings revealed sex-specific strategies to cope with replication stress in PBL from older individuals, namely through DNA damage tolerance pathway switching in women and PARP activation in men, differentially contributing to the decline of genomic stability with age.
衰老相关疾病的发病率各异以及预期寿命的性别差异表明，两性在衰老过程中存在差异。然而，对于衰老的关键因素——基因组不稳定性中的性别特异性差异，我们却知之甚少。在此，我们分析了来自不同年龄的女性和男性供体的循环外周血淋巴细胞（PBL）以及造血干细胞和祖细胞（HSPC）中的DNA损伤反应（DDR），重点关注复制应激。转录组学揭示了衰老过程中DDR途径中显著的性别依赖性表达变化。特别是，参与DNA修复和复制叉重塑的各种DDR成分在男性中随年龄增长而上调。在老年女性中，功能分析表明范可尼贫血途径的活性降低。对复制动力学、增殖细胞核抗原（PCNA）泛素化、跨损伤合成（TLS）-聚合酶信号以及对TLS-聚合酶抑制剂的敏感性分析表明，存在从叉重塑向诱导非经典复制应激的快速TLS的转变。虽然复制动力学未改变且复制应激反而降低，但老年男性的PBL高度依赖聚（ADP-核糖）聚合酶（PARP）活性。总之，我们的研究结果揭示了老年个体PBL中应对复制应激的性别特异性策略，即女性通过DNA损伤耐受途径转换，男性通过PARP激活，这对基因组稳定性随年龄下降有不同的影响。
