Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Department of Biosciences, University of Milan, via Celoria 26, 20133 Milan, Italy.
Mutat Res Rev Mutat Res. 2018 Apr-Jun;776:1-9. doi: 10.1016/j.mrrev.2018.03.004. Epub 2018 Mar 19.
Cell cycle and apoptosis regulator 2 (CCAR2 or DBC1) is a human protein recently emerged as a novel and important player of the DNA damage response (DDR). Indeed, upon genotoxic stress, CCAR2, phosphorylated by the apical DDR kinases ATM and ATR, increases its binding to the NAD+-dependent histone deacetylase SIRT1 and inhibits SIRT1 activity. This event promotes the acetylation and activation of p53, a SIRT1 target, and the subsequent induction of p53 dependent apoptosis. In addition, CCAR2 influences DNA repair pathway choice and promotes the chromatin relaxation necessary for the repair of heterochromatic DNA lesions. However, besides DDR, CCAR2 is involved in several other cellular functions. Indeed, through the interaction with transcription factors, nuclear receptors, epigenetic modifiers and RNA polymerase II, CCAR2 regulates transcription and transcript elongation. Moreover, promoting Rev-erbα protein stability and repressing BMAL1 and CLOCK expression, it was reported to modulate the circadian rhythm. Through SIRT1 inhibition, CCAR2 is also involved in metabolism control and, suppressing RelB and p65 activities in the NFkB pathway, it restricts B cell proliferation and immunoglobulin production. Notably, CCAR2 expression is deregulated in several tumors and, compared to the non-neoplastic counterpart, it may be up- or down-regulated. Since its up-regulation in cancer patients is usually associated with poor prognosis and its depletion reduces cancer cell growth in vitro, CCAR2 was suggested to act as a tumor promoter. However, there is also evidence that CCAR2 functions as a tumor suppressor and therefore its role in cancer formation and progression is still unclear. In this review we discuss CCAR2 functions in the DDR and its multiple biological activities in unstressed cells.
细胞周期和凋亡调节因子 2（CCAR2 或 DBC1）是一种人类蛋白质，最近被认为是 DNA 损伤反应（DDR）的一个新的重要参与者。事实上，在遗传毒性应激下，CCAR2 被顶端 DDR 激酶 ATM 和 ATR 磷酸化后，增加其与 NAD+-依赖性组蛋白去乙酰化酶 SIRT1 的结合，并抑制 SIRT1 活性。这一事件促进了 SIRT1 靶标 p53 的乙酰化和激活，以及随后诱导 p53 依赖性细胞凋亡。此外，CCAR2 影响 DNA 修复途径的选择，并促进染色质松弛，这是修复异染色质 DNA 损伤所必需的。然而，除了 DDR，CCAR2 还参与了几种其他的细胞功能。事实上，通过与转录因子、核受体、表观遗传修饰剂和 RNA 聚合酶 II 的相互作用，CCAR2 调节转录和转录延伸。此外，通过促进 Rev-erbα 蛋白稳定性和抑制 BMAL1 和 CLOCK 的表达，它被报道可以调节生物钟。通过抑制 SIRT1，CCAR2 也参与代谢控制，通过抑制 NFkB 通路中的 RelB 和 p65 活性，它限制了 B 细胞的增殖和免疫球蛋白的产生。值得注意的是，CCAR2 的表达在几种肿瘤中失调，与非肿瘤对应物相比，它可能上调或下调。由于其在癌症患者中的上调通常与预后不良相关，并且其缺失减少了体外癌细胞的生长，因此 CCAR2 被认为是一种肿瘤促进剂。然而，也有证据表明 CCAR2 作为一种肿瘤抑制因子发挥作用，因此其在癌症形成和进展中的作用仍不清楚。在这篇综述中，我们讨论了 CCAR2 在 DDR 中的功能以及其在未受应激的细胞中的多种生物学活性。
