LRRK2 interacts with ATM and regulates Mdm2-p53 cell proliferation axis in response to genotoxic stress.

Abstract

Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin. We found that DNA damage enhances LRRK2 phosphorylation at Serine 910, Serine 935 and Serine 1292. We further showed that LRRK2 phosphorylation is abolished in the absence of ATM, suggesting that LRRK2 phosphorylation requires ATM. It should also be noted that LRRK2 interacts with ATM. In contrast, overexpression or knockdown of LRRK2 does not affect ATM phosphorylation, indicating that LRRK2 is the downstream target of ATM in response to DNA damage. Moreover, we demonstrated that LRRK2 increases the expression of p53 and p21 by increasing the Mdm2 phosphorylation in response to DNA damage. Loss-of-function in LRRK2 has the opposite effect to that of LRRK2. In addition, FACS analysis revealed that LRRK2 enhances cell cycle progression into S phase in response to DNA damage, a finding that was confirmed by 5-bromo-2'-deoxyuridine immunostaining. Taken together, our findings demonstrate that LRRK2 plays an important role in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage.

• Authors: Zhongcan Chen, Zhen Cao, Wei Zhang, Minxia Gu, Zhi Dong Zhou, Baojie Li, Jing Li, Eng King Tan, Li Zeng
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 26 Issue 22 Pg. 4494-4505 (11 15 2017) ISSN: 1460-2083 [Electronic] England
• PMID: 28973420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Doxorubicin
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• LRRK2 protein, human
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Cell Cycle Proteins (genetics)
• Cell Division (genetics)
• Cell Proliferation (physiology)
• DNA Damage (genetics, physiology)
• DNA-Binding Proteins (genetics)
• Doxorubicin (pharmacology)
• HEK293 Cells
• Humans
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NIH 3T3 Cells
• Phosphorylation
• Proteolysis
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)