p53R2,a novel p53-controlled ribonucleotide reductase subunit involved in DNA damage repair and its role in tumorigenesis and cancer treatment
会议名称：《2008年中国病理生理学会第十一届肿瘤和第十二届免疫专...》
会议日期：2008年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported by grants from the National Natural Science Foundation of China (30873094) the Scientific Research Foundations of Ministry of Education and Ministry of Human Resources for the Returned Overseas Chinese Scholars (101 and J20070020) Zhejiang Provincial Science and Technology Research Project (2008C23070).
关 键 词：p53R2 Ribonucleotide reductase DNA damage repair tumorigenesis cancer treatment
摘 要：正Human ribonucleotide reductase （hRR） catalyzes the reduction of ribonucleotides to their corresponding deoxyribonucleotides,which are the building blocks for DNA replication and repair. The enzyme is composed of two identical large （hRRM1） and two identical small （hRRM2） subunits,p53R2 is a newly identified p53-inducible protein which has～80%sequence homology with hRRM2.The p53R2 gene contains a p53-binding site in intron 1.The expression ofp53R2,but not hRRM2,is induced by ultraviolet light,r-irradiation or DNA-damaging agents in a p53-dependent manner.Furthermore,p53 can interact with p53R2 and hRRM2 at the protein level to regulate RR activity in response to genomic stress.Cells that fail to make p53R2 are more sensitive to killing by DNA-damaging agents.A study using p53R2 knockout mice showed that impairment of the p53R2-involved DNA repair pathway enhances the frequency of spontaneous mutations and activates p53-dependent apoptotic pathway（s）.These findings lead to the hypothesis that there are two pathways in human cells to supply dNTPs for DNA synthesis:one through the activity of hRRM2,involved in normal maintenance of dNTPs for DNA replication during the S phase in a cell cycle-dependent manner,and the other through p53R2,supplying dNTPs for DNA repair in G0/G1 cells in a p53-dependent manner.Recently,p53R2 has been shown to possess a crucial role in dNTP supply for mtDNA synthesis.The other functions of p53R2,such as facilitates p21 induction of G1 arrest under UV irradiation,are also proposed.The discovery of p53R2 has created much interest in its molecular characteristics and its possible role in tumorigenesis and cancer treatment.Some investigations have shown that alterations of p53R2 may have implication in tumor development and metastasis.The key role of hRR in DNA synthesis and cell growth control has made it an important target for anticancer therapy,p53R2,functioning in p53-dependent DNA repair pathway,may have the potential to be considered as a new therapeutic target for human cancer treatment.Furthermore,because p53R2 and hRRM2 play different roles in cells,inhibitors specific for each subunit could have different clinical values.Of interest,p53R2 and hRRM2 showed different susceptibility to RR inhibitors,such as iron chelators and radical scavengers, which may lead to a new direction in drug design for human cancer treatment.