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Han SH, Hahm SH, Tran AH, et al. A physical association between the human mutY homolog (hMYH) and DNA topoisomerase II-binding protein 1 (hTopBP1) regulates Chk1-induced cell cycle arrest in HEK293 cells. Cell Biosci. 2015;5:50doi: 10.1186/s13578-015-0042-x.
Han, S. H., Hahm, S. H., Tran, A. H., Chung, J. H., Hong, M. K., Paik, H. D., Kim, K. S., & Han, Y. S. (2015). A physical association between the human mutY homolog (hMYH) and DNA topoisomerase II-binding protein 1 (hTopBP1) regulates Chk1-induced cell cycle arrest in HEK293 cells. Cell & bioscience, 550. https://doi.org/10.1186/s13578-015-0042-x
Han, Se Hee, et al. "A physical association between the human mutY homolog (hMYH) and DNA topoisomerase II-binding protein 1 (hTopBP1) regulates Chk1-induced cell cycle arrest in HEK293 cells." Cell & bioscience vol. 5 (2015): 50. doi: https://doi.org/10.1186/s13578-015-0042-x
Han SH, Hahm SH, Tran AH, Chung JH, Hong MK, Paik HD, Kim KS, Han YS. A physical association between the human mutY homolog (hMYH) and DNA topoisomerase II-binding protein 1 (hTopBP1) regulates Chk1-induced cell cycle arrest in HEK293 cells. Cell Biosci. 2015 Aug 27;5:50. doi: 10.1186/s13578-015-0042-x. eCollection 2015. PMID: 26312135; PMCID: PMC4550056.
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Cell Biosci. 2015 Aug 27;5:50. doi: 10.1186/s13578-015-0042-x. eCollection 2015.

A physical association between the human mutY homolog (hMYH) and DNA topoisomerase II-binding protein 1 (hTopBP1) regulates Chk1-induced cell cycle arrest in HEK293 cells.

Cell & bioscience

Se Hee Han, Soo-Hyun Hahm, An Hue Vy Tran, Ji Hyung Chung, Myoung-Ki Hong, Hyun-Dong Paik, Key-Sun Kim, Ye Sun Han

Affiliations

  1. Department of Advanced Technology Fusion, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701 Republic of Korea.
  2. Department of Applied Bioscience, College of Life Science, CHA University, 120 Haeryong-ro, Pocheon, Gyeonggi-do 463-836 Republic of Korea.
  3. Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701 Republic of Korea.
  4. Department of Food Science and Biotechnology of Animal Resources, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701 Republic of Korea.
  5. Center for Neuroscience, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, Republic of Korea.
  6. Department of Advanced Technology Fusion, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701 Republic of Korea ; College of Global Integrated Studies, Division of Interdisciplinary Studies, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701 Republic of Korea.

PMID: 26312135 PMCID: PMC4550056 DOI: 10.1186/s13578-015-0042-x

Abstract

BACKGROUND: Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. The human mutY homolog (hMYH) is a base excision repair DNA glycosylase that excises adenines or 2-hydroxyadenines that are mispaired with guanine or 7,8-dihydro-8-oxoguanine (8-oxoG). hTopBP1 and hMYH were involved in ATR-mediated Chk1 activation, moreover, both of them were associated with ATR and hRad9 which known as checkpoint-involved proteins. Therefore, we investigated whether hTopBP1 interacted with hMYH, and what the function of their interaction is.

RESULTS: We documented the interaction between hTopBP1 and hMYH and showed that this interaction increased in a hydroxyurea-dependent manner. We also mapped the hMYH-interacting region of hTopBP1 (residues 444-991). In addition, we investigated several cell cycle-related proteins and found that co-knockdown of hTopBP1 and hMYH significantly diminished cell cycle arrest due to compromised checkpoint kinase 1 (Chk1) activation. Moreover, we observed that hMYH was essential for the accumulation of hTopBP1 on damaged DNA, where hTopBP1 interacts with hRad9, a component of the Rad9-Hus1-Rad1 complex. The accumulation of hTopBP1 on chromatin and its subsequent interaction with hRad9 lead to cell cycle arrest, a process mediated by Chk1 phosphorylation and ataxia telangiectasia and Rad3-related protein (ATR) activation.

CONCLUSIONS: Our results suggested that hMYH is necessary for the accumulation of hTopBP1 to DNA damage lesion to induce the association of hTopBP1 with 9-1-1 and that the interaction between hMYH and hTopBP1 is essential for Chk1 activation. Therefore, we suggest that the interaction between hMYH and hTopBP1 is crucial for activation of the ATR-mediated cell cycle checkpoint.

Keywords: ATR signaling; Cell cycle arrest; Human Rad9; Human mutY homolog (hMYH); Human topoisomerase II-binding protein 1 (hTopBP1); Phospho-Chk1

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