DNA polymerase β deficiency in the p53 null cerebellum leads to medulloblastoma formation

Journal Article · Mon Oct 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.09.166· OSTI ID:23107792

Kim, Jusik ^[1]; Kim, Jaemi ^[1]; Lee, Youngsoo ^[1]

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1. Genomic Instability Research Center, Ajou University School of Medicine, Suwon (Korea, Republic of)

Highlights: • DNA polymerase β inactivation leads to medulloblastoma formation in the p53 null cerebellum. • The DNA polymerase β null medulloblastoma is histopathologically similar to human medulloblastoma. • DNA polymerase β and Xrcc1 null medulloblastomas show the characteristics of the SHHα subtype. Defects in DNA damage response or repair mechanisms during neurogenesis result in genomic instability, which is causative for several neural defects. These include brain tumors, particularly medulloblastoma, which occurs in the cerebellum with a high incidence in children. We generated an animal model with defective base excision repair during brain development through selective inactivation of DNA polymerase β (Polb) in neuroprogenitor cells. All of Polb conditional knockout mice developed medulloblastoma in a p53 null background, similar to the Xrcc1 and p53 double deficient animal model. XRCC1 is a scaffolding protein which is involved in DNA damage repair and binds to POLB. In both animal models, the histopathological characteristics of the medulloblastoma were similar to those of human classic medulloblastoma. Brain tumor development was slower in the Polb and p53 double null animals than in the Xrcc1 and p53 double knockout animals. Molecular marker analysis suggested that Polb- and Xrcc1-deficient medulloblastomas belonged to the SHHα subtype, underscoring the important role of genomic stability in preventing this devastating pediatric cerebellar tumor.

• OSTI ID: 23107792
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 505; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CEREBELLUM
DNA
DNA DAMAGES
DNA POLYMERASES
MICE
NEOPLASMS
PEDIATRICS