DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion
DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion
复制标题
DOI：
10.1242/jcs.071340
复制
发表时间：
2011-01-01
影响因子：
4
通讯作者：
Campisi, Judith
中科院分区：
文献类型：
--
作者：
Rodier, Francis;Munoz, Denise P.;Campisi, Judith
DNA损伤可以诱导称为细胞衰老的肿瘤抑制反应。受损的衰老细胞永久性地阻止生长，分泌炎性细胞因子和其他蛋白质，并具有含有DNA损伤反应（DDR）蛋白的持久性核病灶。为了了解持续性损伤灶与标记可修复DNA病变的瞬时灶的不同，我们确定了区分瞬时灶与持续性灶的顺序事件，我们称之为“染色质改变增强衰老的DNA片段”（DNA-SCARS）。与短暂病灶不同，DNA-SCARS与PML核小体相关，缺乏DNA修复蛋白RPA和RAD 51，缺乏单链DNA和DNA合成，并积累DDR介导剂CHK 2和p53的活化形式。DNA-SCARS的形成不依赖于p53、pRB和其他几种检查点和修复蛋白，但需要p53和pRb来触发衰老生长停滞。重要的是，DNA-SCARS稳定组分组蛋白H2 AX的消耗不会从DNA-SCARS中消耗53 BP 1，但减少了MDC 1和活化的CHK 2的存在。此外，H2 AX的耗尽减少了p53依赖性衰老生长停滞和p53非依赖性细胞因子分泌。在多种人类细胞类型和小鼠组织严重损伤后也观察到DNA-SCARS，这表明它们可以与其他标记物结合使用以识别衰老细胞。因此，DNA-SCARS是动态形成的不同结构，其在功能上调节衰老表型的多个方面。
DNA damage can induce a tumor suppressive response termed cellular senescence. Damaged senescent cells permanently arrest growth, secrete inflammatory cytokines and other proteins and harbor persistent nuclear foci that contain DNA damage response (DDR) proteins. To understand how persistent damage foci differ from transient foci that mark repairable DNA lesions, we identify sequential events that differentiate transient foci from persistent foci, which we term 'DNA segments with chromatin alterations reinforcing senescence' (DNA-SCARS). Unlike transient foci, DNA-SCARS associate with PML nuclear bodies, lack the DNA repair proteins RPA and RAD51, lack single-stranded DNA and DNA synthesis and accumulate activated forms of the DDR mediators CHK2 and p53. DNA-SCARS form independently of p53, pRB and several other checkpoint and repair proteins but require p53 and pRb to trigger the senescence growth arrest. Importantly, depletion of the DNA-SCARS-stabilizing component histone H2AX did not deplete 53BP1 from DNA-SCARS but diminished the presence of MDC1 and activated CHK2. Furthermore, depletion of H2AX reduced both the p53-dependent senescence growth arrest and p53-independent cytokine secretion. DNA-SCARS were also observed following severe damage to multiple human cell types and mouse tissues, suggesting that they can be used in combination with other markers to identify senescent cells. Thus, DNA-SCARS are dynamically formed distinct structures that functionally regulate multiple aspects of the senescent phenotype.