A matter of delicate balance: Loss and gain of Cockayne syndrome proteins in premature aging and cancer

Abstract

DNA repair genes are critical for preserving genomic stability and it is well established that mutations in DNA repair genes give rise to progeroid diseases due to perturbations in different DNA metabolic activities. Cockayne Syndrome (CS) is an autosomal recessive inheritance caused by inactivating mutations in CSA and CSB genes. This review will primarily focus on the two Cockayne Syndrome proteins, CSA and CSB, primarily known to be involved in Transcription Coupled Repair (TCR). Curiously, dysregulated expression of CS proteins has been shown to exhibit differential health outcomes: lack of CS proteins due to gene mutations invariably leads to complex premature aging phenotypes, while excess of CS proteins is associated with carcinogenesis. Thus it appears that CS genes act as a double-edged sword whose loss or gain of expression leads to premature aging and cancer. Future mechanistic studies on cell and animal models of CS can lead to potential biological targets for interventions in both aging and cancer development processes. Some of these exciting possibilities will be discussed in this review in light of the current literature.

Keywords: Cockayne Syndrome; aging; cancer; premature aging syndromes; transcription coupled repair.

FIGURE 1

Nucleotide excision repair and its two sub-pathways. Global genome repair (GGR): the UV-induced DNA damage is recognized and removed by GGR, that involves several proteins acting in tandem, including the UV-DDB and XPC-RAD23B, involved in damage recognition. Transcription coupled repair (TCR): TCR is triggered when elongating RNA pol II is blocked by DNA damage in the transcribed strand. CSB is involved in the initiation of TCR through recognition of blocked RNA pol II and binding to this complex, followed by recruitment of the other NER proteins CSA, CUL4, RBX1, DDB1 and UVSSA to the damaged site. In both the sub-pathways, XPB and XPD helicases, which are part of TFIIH, are recruited at the lesion for the DNA unwinding. XPA protein maintains the open DNA region containing the damage, which is then cut out by XPF/ERCC1 and XPG endonucleases at the 3′ and 5′ ends of the damaged DNA, respectively. PCNA recruitment next favors the DNA polymerase action in filling in the resulting gap.

FIGURE 2

The biological predictor role of CS proteins. In our model CS proteins, which are alternatively involved in DNA repair or p53 ubiquitination/degradation, act as dose-limiting factors. When a cytotoxic lesion occurs, CS proteins, together with the TCR machinery, are transiently recruited at the level of the stalled RNA pol II, whose backtracking or degradation will allow the repair in case of sub-lethal damage. In this context, p53 is not ubiquitinated and degraded and it is free to induce a transient cell cycle arrest, in those cells receiving sub-lethal DNA damage. Cell cycle will be then restored upon the completion of DNA repair when CS proteins, being no longer engaged in TCR, will be able to re-establish the basal level of p53 through its ubiquitination and degradation. If cells are exposed to lethal damage/stress, instead, they will undergo an irreversible cell cycle arrest followed by apoptosis, due to the sustained activation of p53. In this case, CS proteins accumulate and persist at the damaged sites and, as a result of this entrapment, p53 may not be efficiently degraded [(A,B) central panel]. When CS role as biological predictors is missing, as in the context of CS cells, the lack of p53 degradation leads to a massive induction of apoptosis [(B) left panel]. Instead in cancer cells, where CS proteins are overexpressed, abnormally high levels of p53 degradation are induced, thereby promoting development and progression of cancers, by shifting the cell fate toward survival and proliferation rather than apoptosis [(B) right panel].

FIGURE 3

The balanced action of CS proteins. In normal conditions, CSA and CSB pro-survival activity counterbalances the signaling pathways that, otherwise, would lead to the induction of senescence and the triggering of apoptosis in response to the insults to which the cells are daily exposed (A). Lack of CS proteins due to gene mutations causes an unbalance in which senescence and apoptotic load are not counteracted, thus leading to complex premature aging phenotypes (B). A gain of CS proteins expression, instead, is responsible for an up-regulation of pro-survival pathways, thus favoring conditions for cancer development and progression (C).