Brosh Robert M, Wu Yuliang
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
NAR Cancer. 2021 Aug 20;3(3):zcab034. doi: 10.1093/narcan/zcab034. eCollection 2021 Sep.
A well-accepted hallmark of cancer is genomic instability, which drives tumorigenesis. Therefore, understanding the molecular and cellular defects that destabilize chromosomal integrity is paramount to cancer diagnosis, treatment and cure. DNA repair and the replication stress response are overarching paradigms for maintenance of genomic stability, but the devil is in the details. ATP-dependent helicases serve to unwind DNA so it is replicated, transcribed, recombined and repaired efficiently through coordination with other nucleic acid binding and metabolizing proteins. Alternatively folded DNA structures deviating from the conventional anti-parallel double helix pose serious challenges to normal genomic transactions. Accumulating evidence suggests that G-quadruplex (G4) DNA is problematic for replication. Although there are multiple human DNA helicases that can resolve G4 , it is debated which helicases are truly important to resolve such structures . Recent advances have begun to elucidate the principal helicase actors, particularly in cellular DNA replication. FANCJ, a DNA helicase implicated in cancer and the chromosomal instability disorder Fanconi Anemia, takes center stage in G4 resolution to allow smooth DNA replication. We will discuss FANCJ's role with its protein partner RPA to remove G4 obstacles during DNA synthesis, highlighting very recent advances and implications for cancer therapy.
基因组不稳定是被广泛认可的癌症标志之一，它驱动肿瘤发生。因此，了解破坏染色体完整性的分子和细胞缺陷对于癌症的诊断、治疗和治愈至关重要。DNA修复和复制应激反应是维持基因组稳定性的总体范式，但细节决定成败。ATP依赖的解旋酶用于解开DNA，使其通过与其他核酸结合和代谢蛋白的协调而有效地进行复制、转录、重组和修复。偏离传统反平行双螺旋的另类折叠DNA结构对正常基因组事务构成严重挑战。越来越多的证据表明，G-四链体（G4）DNA对复制存在问题。虽然有多种人类DNA解旋酶可以解开G4，但对于哪些解旋酶对解决此类结构真正重要仍存在争议。最近的进展已开始阐明主要的解旋酶角色，特别是在细胞DNA复制方面。FANCJ是一种与癌症和染色体不稳定疾病范可尼贫血相关的DNA解旋酶，在解决G4以实现顺利的DNA复制过程中占据核心地位。我们将讨论FANCJ与其蛋白伴侣RPA在DNA合成过程中清除G4障碍的作用，重点介绍最新进展及其对癌症治疗的意义。
