Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, The University of Texas at Austin, Austin, Texas, USA.
Department of Chemistry, University of Utah, Salt Lake City, Utah, USA.
Bioessays. 2022 Jul;44(7):e2200015. doi: 10.1002/bies.202200015. Epub 2022 May 9.
The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNA repair. Indeed, KDM5A engages poly(ADP-ribose) (PAR) chains at damage sites through a previously uncharacterized coiled-coil domain, a novel binding mode for PAR interactions. While KDM5A is a well-known transcriptional regulator, its function in DNA repair is only now emerging. Here we review the molecular mechanisms that regulate this PARP1-macroH2A1.2-KDM5A axis in DNA damage and consider the potential involvement of this pathway in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA-based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies.
赖氨酸去甲基酶 KDM5A 与 PARP1 和组蛋白变体 macroH2A1.2 合作，调节染色质以促进 DNA 修复。事实上，KDM5A 通过以前未被表征的卷曲螺旋结构域与损伤部位的聚（ADP-核糖）（PAR）链结合，这是 PAR 相互作用的一种新结合模式。虽然 KDM5A 是一种众所周知的转录调节剂，但它在 DNA 修复中的作用直到现在才显现出来。在这里，我们综述了调控这个 PARP1-macroH2A1.2-KDM5A 轴在 DNA 损伤中的分子机制，并考虑了该途径在转录调控和癌症中的潜在作用。我们以 KDM5A 为例，讨论了多功能染色质蛋白如何在几种基于 DNA 的过程之间转换，这些过程必须协调一致，以保护基因组和表观基因组的完整性。在包括癌症在内的人类疾病中普遍存在的染色质失调和基因组完整性丧失可能存在关联，并可能为靶向这些途径的多功能蛋白提供治疗策略的机会。
