Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2.
Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2.
复制标题
DOI：
10.1016/j.devcel.2016.05.004
复制
发表时间：
2016-06-06
影响因子：
11.8
通讯作者：
Fox DT
中科院分区：
文献类型：
--
作者：
Bretscher HS;Fox DT
保守的DNA损伤反应（DDRs）检测基因组损伤并防止断裂染色体的有丝分裂。缺乏DDRs的细胞如何在有丝分裂过程中科普断裂的染色体尚不清楚。在具有额外基因组的细胞中，DDRs经常失活（多倍体），这表明对多倍体的研究可以揭示具有受损DDRs/基因组损伤的细胞如何继续分裂。在这里，我们表明继续分裂和正常的器官发育发生在多倍体，DDR受损的果蝇乳头细胞。当乳头状细胞变成多倍体时，它们自然地积累断裂的无着丝粒染色体，但不使细胞周期停滞。为了在无着丝粒染色体的有丝分裂中存活，乳头状细胞需要Fanconi贫血蛋白FANCD 2和FANCI以及Blm解旋酶，但不需要典型的DDR信号传导。FANCD 2独立于先前的S期发挥作用，以促进由双链断裂产生的无着丝粒DNA的对齐和分离，从而避免微核和器官畸形。由于多倍性和受损的DDRs可以促进癌症，我们的研究结果为疾病相关的DNA损伤耐受机制提供了见解。
Conserved DNA damage responses (DDRs) sense genome damage and prevent mitosis of broken chromosomes. How cells lacking DDRs cope with broken chromosomes during mitosis is poorly understood. DDRs are frequently inactivated in cells with extra genomes (polyploidy), suggesting study of polyploidy can reveal how cells with impaired DDRs/genome damage continue dividing. Here, we show continued division and normal organ development occurs in polyploid, DDR-impaired Drosophila papillar cells. As papillar cells become polyploid, they naturally accumulate broken acentric chromosomes, but do not apoptose/arrest the cell cycle. To survive mitosis with acentric chromosomes, papillar cells require Fanconi Anemia proteins FANCD2 and FANCI, and Blm helicase, but not canonical DDR signaling. FANCD2 acts independently of previous S-phases to promote alignment and segregation of acentric DNA produced by double-strand breaks, thus avoiding micronuclei and organ malformation. As polyploidy and impaired DDRs can promote cancer, our findings provide insight into disease-relevant DNA damage tolerance mechanisms.