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To investigate molecular controls of cardiomyocyte proliferation, we utilized cardiomyocytes induced to proliferate indefinitely by SV40 large T antigen (T-ag). In the T-ag-immortalized AT-1, AT-2 and HL-1 cardiomyocytes, normal cellular proteins associating with T-ag and p53 were identified, isolated and micro-sequenced. Peptide sequencing revealed that proteins of 90, 100 and 160 kDa were homologs of MRE11, NBS1 and RAD50, respectively. These three proteins play critical roles in the detection and repair of DNA double-strand breaks, activation of cell cycle checkpoints and telomere maintenance. In this report, we describe the cDNA cloning and double-strand sequencing of the rat homologs of MRE11, NBS1 and RAD50. We also determined the mRNA and protein levels of MRE11, NBS1 and RAD50 at different stages of heart development and in different tissues. MRE11 mRNA was only detected in the immortalized cardiomyocytes and in the testes. Although the 90 kDa MRE11 protein was seen in most samples examined, it was only detected at extremely low levels in proliferating cardiomyocytes (normal and immortalized). The 6.0 kb MRE11-related mRNA transcript (MRT) was seen in all samples examined. Levels of both NBS1 and RAD50 mRNA transcripts peaked in the heart at postnatal day 10. NBS1 mRNA levels were at very low levels in the T-ag-immortalized AT-1, AT-2 and HL-1 cells but NBS1 protein was observed at extremely high levels. We propose that SV40 large T antigen's interaction with the MRE11-NBS1-RAD50 pathway and with p53 ablates critical cell cycle checkpoints and that this is one of the major factors involved in the ability of this oncoprotein to immortalize cardiomyocytes.

The MRE11-NBS1-RAD50 pathway is perturbed in SV40 large T antigen-immortalized AT-1, AT-2 and HL-1 cardiomyocytes