Frontini Mattia, Proietti-De-Santis Luca
Department of Haematology, University of Cambridge, CB2 0PT, Cambridge, United Kingdom.
Aging (Albany NY). 2012 Feb;4(2):89-97. doi: 10.18632/aging.100439.
The CSB protein plays a role in the transcription coupled repair (TCR) branch of the nucleotide excision repair pathway. CSB is very often found mutated in Cockayne syndrome, a segmental progeroid genetic disease characterized by organ degeneration and growth failure. The tumor suppressor p53 plays a pivotal role in triggering senescence and apoptosis and suppressing tumorigenesis. Although p53 is very important to avoid cancer, its excessive activity can be detrimental for the lifespan of the organism. This is why a network of positive and negative feedback loops, which most likely evolved to fine-tune the activity of this tumor suppressor, modulate its induction and activation. Accordingly, an unbalanced p53 activity gives rise to premature aging or cancer. The physical interaction between CSB and p53 proteins has been known for more than a decade but, despite several hypotheses, nobody has been able to show the functional consequences of this interaction. In this review we resume recent advances towards a more comprehensive understanding of the critical role of this interaction in modulating p53’s levels and activity, therefore helping the system find a reasonable equilibrium between the beneficial and the detrimental effects of its activity. This crosstalk re-establishes the physiological balance towards cell proliferation and survival instead of towards cell death, after stressors of a broad nature. Accordingly, cells bearing mutations in the csb gene are unable to re-establish this physiological balance and to properly respond to some stress stimuli and undergo massive apoptosis.
CSB蛋白在核苷酸切除修复途径的转录偶联修复（TCR）分支中发挥作用。CSB经常在科凯恩综合征中发生突变，这是一种节段性早衰性遗传病，其特征为器官退化和生长发育迟缓。肿瘤抑制因子p53在触发细胞衰老和凋亡以及抑制肿瘤发生过程中起着关键作用。尽管p53对预防癌症非常重要，但其过度活跃可能对生物体的寿命有害。这就是为什么一个由正负反馈环组成的网络（很可能是为了微调这种肿瘤抑制因子的活性而进化而来）会调节其诱导和激活。因此，p53活性失衡会导致早衰或癌症。CSB蛋白和p53蛋白之间的物理相互作用已为人所知超过十年，但尽管有几种假说，却没有人能够证明这种相互作用的功能后果。在这篇综述中，我们总结了最近在更全面理解这种相互作用在调节p53水平和活性方面的关键作用方面取得的进展，从而帮助该系统在其活性产生的有益和有害影响之间找到合理的平衡。这种相互作用在多种性质的应激源作用后，重新建立了有利于细胞增殖和存活而非细胞死亡的生理平衡。因此，携带csb基因突变的细胞无法重新建立这种生理平衡，并对某些应激刺激无法做出适当反应，从而发生大量细胞凋亡。
