DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis

Bernstein, Carol; Bernstein, Harris; Payne, Claire M.; Garewal, Harinder S.

doi:10.1016/s1383-5742(02)00009-1

Cited by 470 publications

(313 citation statements)

References 248 publications

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“…Therefore, to fully engage in the execution of apoptosis, the cells must also degrade the key proteins involved in the DNA repair processes. 31 It has been reported that, at early stages of apoptosis, DNaseY can be inactivated by PARP-1 through the poly-ADPribosylation mechanism. 18,19 Here we found a significant upregulation of PARP-1 in the DNaseY-overexpressing cells (Figure 11a).…”

Section: Discussionmentioning

confidence: 99%

Regulation of DNaseY activity by actinin-α4 during apoptosis

et al. 2004

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DNaseY, a Ca 2 þ -and Mg 2 þ -dependent endonuclease, has been implicated in apoptotic DNA degradation; however, the molecular mechanisms controlling its involvement in this process have not been fully elucidated. We have obtained evidence from yeast two-hybrid screening and coimmunoprecipitation experiments that DNaseY interacted physically with actinin-a4 and this interaction significantly enhanced its endonuclease activity. Accordingly, simultaneous overexpression of both proteins in PC12 cells dramatically increased the rate of apoptosis in response to teniposide' VM26. However, overexpression of DNaseY alone neither triggered apoptosis nor facilitated cell death in response to VM26 or serum deprivation. Instead, the overexpression of DNaseY increased the production of single-strand DNA breaks and evoked a profound upregulation of DNA repair pathways. Taken together, our results point to a novel regulatory mechanism of DNaseY activity and offer an explanation for why cells must first cleave key DNA repair and replication proteins before the successful execution of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Regulation of DNaseY activity by actinin-α4 during apoptosis

et al. 2004

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“…A possible explanation is that damaged p53-deficient cells were able to cycle but were more impaired than wild-type cells in the progression through S and G 2 M phases, possibly because of less efficient repair. 32 Cells of both lines treated with DXR while in S and G 2 M and that reached G 2 M in the first hours after treatment, were strongly intercepted by the G 2 M checkpoint. This confirmed that even though p53 contributes to G 2 M arrest in response to DNA damage, p53-independent pathways are also important in the activation of this checkpoint.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 93%

The Contribution of p53 in the Dynamics of Cell Cycle Response to DNA Damage Interpreted by a Mathematical Model

Lupi¹,

Matera²,

Natoli³

et al. 2007

Cell Cycle

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AbbreViAtioNs AbstrACtDespite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G 1 , S and G 2 M phases after drug treatment is lacking. We tackled the analysis of the complexity of cell cycle effects combining the time-course measures with different techniques with the aid of a computer program simulating cell cycle progression. This mixed experimental-simulation approach enabled us to decode the dynamics of the cytostatic and cytotoxic responses to cisplatin and doxorubicin treatments in a p53-proficient colon carcinoma cell line (HCT-116) and in its p53-deficient counterpart. We achieved a separate evaluation of the activity of each cell cycle control and we connected these results with measures of p53 level in G 1 , S and G 2 M.We confirmed the action of p53 in all cell cycle phases, but also the presence of strong p53-independent cytostatic and cytotoxic activities exerted by both drugs. In G 1 phase, p53 was responsible for a medium/long term block, distinct from the short-term block, which was p53-independent. The delay in traversing S phase was reduced by the presence of p53. In G 2 M phase, despite a strong p53-independent block, there was a weaker but more persistent p53-dependent block. At cytotoxic concentrations, p53-dependent and p53-independent cell death was observed. The former was poorly phase-specific, occurred earlier and exploited the apoptotic mechanism more than p53-independent death.Computer simulation produced a framework where previous partial and sometimes apparently contradictory observations of the p53-mediated effects could be reconciled and explained.

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“…Over the last few years, it has become clear that telomere shortening is probably a minor factor in the initiation of genomic instability, although telomerase reactivation probably plays an important role in tumor progression. 28 DNA repair defects 29 or fragile sites 30 have alternatively been suggested to initiate genetic instability. In contrast to a proposed repair defect, many CIN tumors show upregulation of DSB repair pathways such as non-homologous end joining.…”

Section: Are Aneuploidy and Chromosome Breakage Caused By A Cingle Mementioning

confidence: 99%

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Martı́nez-A

Wely

2010

Cell Cycle

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G enetic instability is a hallmark of cancer. Most tumors show complex patterns of translocations, amplifications and deletions, which have occupied scientists for decades. A specific problem arises in carcinomas with a genetic defect termed chromosomal instability; these solid tumors undergo gains and losses of entire chromosomes, as well as segmental defects caused by chromosome breaks. To date, the apparent inconsistency between intact and broken chromosomes has precluded identification of an underlying mechanism. The recent identification of centromeric breaks alongside aneuploidy in cells with spindle defects indicates that a single mechanism could account for all genetic alterations characteristic of chromosomal instability. Since a poorly controlled spindle can cause merotelic attachments, kinetochore distortion and subsequent chromosome breakage, spindle defects can generate the sticky ends necessary to start a breakagefusion-bridge cycle. The characteristic breakpoint of spindle-generated damage, adjacent to the centromere, also explains the losses and gains of whole chromosome arms, which are especially prominent in low-grade tumors. The recent data indicate that spindle defects are an early event in tumor formation, and an important initiator of carcinogenesis.

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DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis

Cited by 470 publications

References 248 publications

Regulation of DNaseY activity by actinin-α4 during apoptosis

Regulation of DNaseY activity by actinin-α4 during apoptosis

The Contribution of p53 in the Dynamics of Cell Cycle Response to DNA Damage Interpreted by a Mathematical Model

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

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