University of Konstanz, Molecular Toxicology Group, Department of Biology, D-78457 Konstanz, Germany.
University of Konstanz, Molecular Toxicology Group, Department of Biology, D-78457 Konstanz, Germany.
Ageing Res Rev. 2015 Sep;23(Pt A):12-28. doi: 10.1016/j.arr.2014.12.006. Epub 2014 Dec 30.
Genome instability represents a primary hallmark of aging and cancer. RecQL helicases (i.e., RECQL1, WRN, BLM, RECQL4, RECQL5) as well as poly(ADP-ribose) polymerases (PARPs, in particular PARP1) represent two central quality control systems to preserve genome integrity in mammalian cells. Consistently, both enzymatic families have been linked to mechanisms of aging and carcinogenesis in mice and humans. This is in accordance with clinical and epidemiological findings demonstrating that defects in three RecQL helicases, i.e., WRN, BLM, RECQL4, are related to human progeroid and cancer predisposition syndromes, i.e., Werner, Bloom, and Rothmund Thomson syndrome, respectively. Moreover, PARP1 hypomorphy is associated with a higher risk for certain types of cancer. On a molecular level, RecQL helicases and PARP1 are involved in the control of DNA repair, telomere maintenance, and replicative stress. Notably, over the last decade, it became apparent that all five RecQL helicases physically or functionally interact with PARP1 and/or its enzymatic product poly(ADP-ribose) (PAR). Furthermore, a profound body of evidence revealed that the cooperative function of RECQLs and PARP1 represents an important factor for maintaining genome integrity. In this review, we summarize the status quo of this molecular cooperation and discuss open questions that provide a basis for future studies to dissect the cooperative functions of RecQL helicases and PARP1 in aging and carcinogenesis.
基因组不稳定性是衰老和癌症的主要标志之一。RecQ 解旋酶（即 RECQL1、WRN、BLM、RECQL4、RECQL5）和聚（ADP-核糖）聚合酶（PARPs，尤其是 PARP1）是维持哺乳动物细胞基因组完整性的两个主要质量控制系统。一致地，这两个酶家族都与小鼠和人类的衰老和致癌机制有关。这与临床和流行病学研究结果一致，这些研究表明，三种 RecQ 解旋酶（WRN、BLM、RECQL4）的缺陷与人类早衰和癌症易感性综合征有关，分别为 Werner、Bloom 和 Rothmund-Thomson 综合征。此外，PARP1 功能低下与某些类型癌症的风险增加有关。在分子水平上，RecQ 解旋酶和 PARP1 参与控制 DNA 修复、端粒维持和复制应激。值得注意的是，在过去的十年中，已经明显表明所有五种 RecQ 解旋酶都与 PARP1 及其酶产物聚（ADP-核糖）（PAR）在物理上或功能上相互作用。此外，大量证据表明，RECQLs 和 PARP1 的协同功能是维持基因组完整性的一个重要因素。在这篇综述中，我们总结了这种分子相互作用的现状，并讨论了一些悬而未决的问题，为未来研究解析 RecQ 解旋酶和 PARP1 在衰老和致癌中的协同功能提供了基础。
