Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers.

Chen Yang,Anders Näsman,Franziska Ragaller,Mingzhi Liu,Ahmed Waraky,Joseph Carlson,Olle Larsson,Yifan Zhang,Sara Corvigno,Yi Chen,Hanna Dahlstrand,Zihua Chen,Felix Haglund,Yingbo Lin,Komaraiah Palle

doi:10.1371/journal.pone.0236291

Abstract

Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.

Highlights

During cell division numerous events may hinder the accurate and complete replication of the genome, commonly referred to as replication stress
We believe that the IGF1R/proliferating cell nuclear antigen (PCNA) interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability
These results indicate that the IGF1R/PCNA colocalization is upregulated in a subset of clinical cancers

Summary

Introduction

During cell division numerous events may hinder the accurate and complete replication of the genome, commonly referred to as replication stress. Faulty DNA repair systems (including mismatch repair, recombinational repair, nucleotide excision repair or base excision repair) frequently result in accelerated genome destabilization [2]. To overcome this complication, cancer cells may utilize DNA maintenance protocols to guarantee genomic replication in face of endogenous and exogenous replication stress [3, 4]. The DNA damage tolerance (DDT) pathway has recently been recognized as a mechanism to overcome replication stress induced fork stalling either by error-prone translesion synthesis (TLS) or error-free template switching (TS) [5, 6]. A key mediator of DDT is the DNA clamp proliferating cell nuclear antigen (PCNA) which functions by recruiting proteins to the DNA

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