Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer

Wenjun Hu,Linping Lei,Xuqin Xie,Libin Huang,Qian Cui,Tang Dang,Gang Logan Liu,Yuan Li,Xiaofeng Sun,Zongguang Zhou

doi:10.1038/s41419-019-1784-x

Wenjun Hu, Linping Lei + Show 8 more

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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.

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world and is a leading cause of cancer-related mortality for both males and females[1]
HnRNP L is involved in the DNA damage response, including activation-induced cytidine deaminase (AID)-induced class switch recombination (CSR) of B cells and genome instability of CRC cells To examine the role of Heterogeneous nuclear ribonucleoprotein L (hnRNP L) during CSR, we introduced RNAi oligonucleotides into CH12F3-2A cells to knockdown hnRNP L or AID (Fig. 1a)
This function of hnRNP L is inferred to be universal since enhanced double-strand breaks (DSBs) signals were observed in both CIT-stimulated CH12F3-2A cells and in oxaliplatintreated CRC cells with depleted hnRNP L

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world and is a leading cause of cancer-related mortality for both males and females[1]. Oxaliplatin, a platinum-based anti-neoplastic drug, is one of the most effective chemotherapeutic drugs used for the treatment of CRC2. It exhibits high double-stranded DNA crosslinking activity, thereby impairing DNA replication and transcription[7,8,9], eventually leading to substantial DNA double-strand breaks (DSBs) and cell apoptosis. Hu et al Cell Death and Disease (2019)10:550 oxaliplatin-induced cell death and show high tolerance and acquired resistance to this drug[10] In this regard, it has been found that DSBs repair is one of the critical factors responsible for resistance to chemotherapy in many cancers[11,12]. Novel strategies designed to impair DNA repair may contribute to enhancing the chemosensitivity to oxaliplatin in CRC treatment

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