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Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer
Sichuan Univ, Peoples R China.
Sichuan Univ, Peoples R China.
Sichuan Univ, Peoples R China.
Sichuan Univ, Peoples R China.
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2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 550Article in journal (Refereed) Published
Abstract [en]

Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), tumor cells can develop mechanisms to evade oxaliplatin-induced cell death and show high tolerance and acquired resistance to this drug. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) has been proved to play a critical role in DNA repair during IgH class switch recombination (CSR) in B lymphocytes, while, its role in CRC and chemotherapeutic resistance remain unknown. Our study aims to uncover an unidentified mechanism of regulating DNA double-strand breaks (DSBs) by hnRNP L in CRC cells treated by oxaliplatin. In present study, we observed that knockdown of hnRNP L enhanced the level of DNA breakage and sensitivity of CRC cells to oxaliplatin. The expression of key DNA repair factors (BRCA1, 53BP1, and ATM) was unaffected by hnRNP L knockdown, thereby excluding the likelihood of hnRNP L mediation via mRNA regulation. Moreover, we observed that phosphorylation level of ATM changed oppositely to 53BP1 and BRCA1 in the CRC cells (SW620 and HCT116) which exhibit synergistic effect by oxaliplatin plus hnRNP L impairment. And similar phenomenon was observed in the foci formation of these critical repair factors. We also found that hnRNP L binds directly with these DNA repair factors through its RNA-recognition motifs (RRMs). Analysis of cell death indicated that the RRMs of hnRNP L are required for cell survival under incubation with oxaliplatin. In conclusion, hnRNP L is critical for the recruitment of the DNA repair factors in oxaliplatin-induced DSBs. Targeting hnRNP L is a promising new clinical approach that could enhance the effectiveness of current chemotherapeutic treatment in patients with resistance to oxaliplatin.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 10, article id 550
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-159243DOI: 10.1038/s41419-019-1784-xISI: 000476593700008PubMedID: 31320608OAI: oai:DiVA.org:liu-159243DiVA, id: diva2:1341277
Note

Funding Agencies|National Nature Science Foundation of China [81602111]; China Postdoctoral Science Foundation [2016M592675]; National Key RD Plan [2016YFC0906001-2]

Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-08

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Sun, Xiao-Feng
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Oncology
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