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N-methylpurine DNA Glycosylase (MPG) Inhibits P53-mediated Cell Cycle Arrest and Coordinates with P53to Determine Sensitivity to Alkylating Agents

Author: SongShanShan
Tutor: HeFuChu
School: Beijing Union Medical College
Course: Genetics
Keywords: MPG p53 cell cycle arrest base excision repair alkylating agents
CLC: R730.2
Type: PhD thesis
Year: 2012
Downloads: 80
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p53is one of the most studied tumor suppressors in the cancer research field. Extensive mutation searches demonstrated that over50%of human tumors carry p53mutations. It is widely accepted that p53is a sequence-specific transcription factor and plays a pivotal role in the regulation of cell cycle progression, apoptosis and DNA repair in response to diverse stress signals. In unstressed conditions, p53is kept at an extremely low level due to rapid proteasomal degradation. When under stress, however, p53is stabilized and released from suppression. There are at least two ways in which p53is activated:posttranslational modifications and interactions with various proteins. A few proteins have been identified that associate with p53to selectively regulate the expression of p53downstream targets. In unstressed conditions, the regulation of p53-mediated cell cycle arrest, particularly the negative regulation, is still not fully understood.To search for novel regulators of p53, we used high-density protein microarrays. Among the novel potential p53-interacting proteins, we found that N-methylpurine DNA glycosylase (MPG, also called AAG or ANPG), the first identified enzyme in the base excision repair (BER) pathway, can bind to p53and selectively repress p53-mediated cell cycle arrest in cancer cells under unstressed situations.As a core enzyme in BER, MPG has been shown to recognize and excise a broad range of modified bases, in addition to normal bases, in DNA. The removal of bases leaves repair intermediates, abasic (apurinic/apyrimidic) AP sites, which are cytotoxic and mutagenic, which makes it apparent that the removal of these BER intermediates is crucial. Alkylating agents have been frequently used in the treatment of human cancers.The major DNA damage produced by alkylating agents is recognized and repaired by MPG.Our current findings show that the MPG N-terminus plays an important role for p53binding and regulation. MPG specifically inhibits p53-mediated cell cycle arrest but not apoptosis. In response to alkylation damage, in p53wild-type tumor cells, MPG dissociated from p53, resulting in the release of p53and cell cycle arrest to repair damaged bases. Then, high MPG combination with wild-type p53in certain tumor cells led to insensitivity to alkylating agents. By contrast, in p53-mutated cells, the AP sites were repaired with low efficacy and the killing effects were higher than the p53wild-type cells. Therefore, MPG coordinates its glycosylase and non-glycosylase modules to participate in the DNA damage repair. Also, the p53status coordinates with MPG to play a pivotal role in determination of cancer sensitivity to alkylating drugs. To our knowledge, this is the first direct evidence to show that a DNA repair enzyme functions as a selective regulator of p53, and these findings provide new insights into functional linkage between MPG and p53in the cancer therapy.

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CLC: > Medicine, health > Oncology > General issues > Tumor pathology, etiology
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