Lezaja Aleksandra, Panagopoulos Andreas, Wen Yanlin, Carvalho Edison, Imhof Ralph, Altmeyer Matthias
Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
Nat Commun. 2021 Jun 22;12(1):3827. doi: 10.1038/s41467-021-23806-5.
The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control. How such inherited lesions affect genome function and integrity is not well understood. Here, we identify a new class of heritable DNA lesions, which is marked by replication protein A (RPA), a protein primarily known for shielding single-stranded DNA in S/G2. We demonstrate that post-mitotic RPA foci occur at low frequency during unperturbed cell cycle progression, originate from the previous cell cycle, and are exacerbated upon replication stress. RPA-marked inherited ssDNA lesions are found at telomeres, particularly of ALT-positive cancer cells. We reveal that RPA protects these replication remnants in G1 to allow for post-mitotic DNA synthesis (post-MiDAS). Given that ALT-positive cancer cells exhibit high levels of replication stress and telomere fragility, targeting post-MiDAS might be a new therapeutic opportunity.
检查点使细胞周期进程停滞以进行基因组修复的范式，已受到近期关于可遗传DNA损伤逃避检查点控制这一发现的挑战。此类遗传损伤如何影响基因组功能和完整性尚不清楚。在此，我们鉴定出一类新的可遗传DNA损伤，其以复制蛋白A（RPA）为标记，RPA是一种主要在S/G2期用于保护单链DNA的蛋白质。我们证明，在未受干扰的细胞周期进程中，有丝分裂后RPA病灶以低频率出现，起源于前一个细胞周期，并在复制应激时加剧。RPA标记的遗传性单链DNA损伤存在于端粒，尤其是在ALT阳性癌细胞中。我们发现，RPA在G1期保护这些复制残余物，以允许有丝分裂后DNA合成（有丝分裂后DNA合成，post-MiDAS）。鉴于ALT阳性癌细胞表现出高水平的复制应激和端粒脆性，靶向有丝分裂后DNA合成可能是一个新的治疗机会。
