repository
The role of DNA polymerase β, one of main factors in base excision repair, in the nervous system
- Author(s)
- 김주식
- Advisor
- 이영수
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2020-08
- Language
- eng
- Keyword
- ATM; Cerebellar ataxia; Medulloblastoma; POLB; p53
- Alternative Abstract
- Base excision repair pathway plays important roles in repairing damaged DNA bases or removing chemically modified DNA bases during DNA demethylation process for gene expression. POLB is one of key enzymes for this DNA repair pathway, which acts as a DNA lyase and DNA polymerase at DNA damage sites through binding to XRCC1. XRCC1 is a scaffolding protein and has a crucial role for recruiting several DNA repair proteins to the sites of damaged bases or strand breaks. Human XRCC1 mutations are responsible for the spinocerebellar ataxia 26 and the deletion of the Xrcc1 gene in the murine nervous system led to several neurological phenotypes including the loss of cerebellar interneurons. Interestingly, the severe cerebellar ataxia due to abnormal cerebellar development was observed in the Xrcc1/Atm double null animal model. A protein kinase ATM responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia (A–T), which is characterized by progressive cerebellar ataxia. It is not fully understood yet the molecular mechanisms of the DNA damage repair defects and cerebellar ataxia, although several human genetic diseases as exemplified above indicate the strong connection between those two. So the working hypothesis was POLB is the responsible protein for the XRCC1 related neurologic phenotypes. To study the connection between POLB and XRCC1 in the nervous system, an animal model of selective Polb inactivation during neurogenesis was generated and examined. In contrast to Xrcc1 deficiency in the murine nervous system, inactivation of Polb affected only a subpopulation of cortical intereurons despite the accumulation of DNA damage throughout the brain, and there was no sign of cerebellar interneuron loss. The dual inactivation of Polb and Atm resulted in cerebellar ataxia without significant neuropathological defects, which was different from the Xrcc1 and Atm inactivated animal model. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle, in which POLB is involved, and reduced enzyme activity of methylcytosine hydroxylase TET1 that could be activated by ATM upon DNA damage. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. These finding suggest defective calcium homeostasis due to dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes. Furthermore, similarly to the Xrcc1 and p53 double null animal model, which develops medulloblastoma, the Polb/p53 animal model also develop the brain tumor. Medulloblastoma, which occurs in the cerebellum with a high incidence in children, is divided into four subgroups dependent on the molecular expression profiles and its origin (WNT, SHH, Group 3, and Group 4). The medulloblastoma due to inactivation of either Polb or Xrcc1 in deletion of p53 background belonged to the SHH type, particularly SHHα subtype verified by the representative gene expressions for that subtype, such as Atoh1, Gli2, Ptch2, and Sfrp1, suggesting that granule cell origin of the medulloblastoma, also underscores the important role of genomic stability in preventing this devastating pediatric cerebellar tumor. My data suggest that POLB is important for cerebral interneuron genesis and cerebellar function by preventing accumulation of endogenous DNA damage and proper DNA methylation cycle.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
- Files in This Item:
- There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.
-
- License
- STATISTICS
- Total Visit :3,300,118
- Total Download :1,737
- Today View :7,936
