Mitotic DNA synthesis is differentially regulated between cancer and noncancerous cells

Cari L Graber-Feesl, Kayla D. Pederson, Katherine J Aney, Naoko Shima

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4 Scopus citations

Abstract

Mitotic DNA synthesis is a recently discovered mechanism that resolves late replication intermediates, thereby supporting cell proliferation under replication stress. This unusual form of DNA synthesis occurs in the absence of RAD51 or BRCA2, which led to the identification of RAD52 as a key player in this process. Notably, mitotic DNA synthesis is predominantly observed at chromosome loci that colocalize with FANCD2 foci. However, the role of this protein in mitotic DNA synthesis remains largely unknown. In this study, we investigated the role of FANCD2 and its interplay with RAD52 in mitotic DNA synthesis using aphidicolin as a universal inducer of this process. After examining eight human cell lines, we provide evidence for FANCD2 rather than RAD52 as a fundamental supporter of mitotic DNA synthesis. In cancer cell lines, FANCD2 exerts this role independently of RAD52. Surprisingly, RAD52 is dispensable for mitotic DNA synthesis in noncancerous cell lines, but these cells strongly depend on FANCD2 for this process. Therefore, RAD52 functions selectively in cancer cells as a secondary regulator in addition to FANCD2 to facilitate mitotic DNA synthesis. As an alternative to aphidicolin, we found partial inhibition of origin licensing as an effective way to induce mitotic DNA synthesis preferentially in cancer cells. Importantly, cancer cells still perform mitotic DNA synthesis by dual regulation of FANCD2 and RAD52 under such conditions. Implications: These key differences in mitotic DNA synthesis between cancer and noncancerous cells advance our understanding of this mechanism and can be exploited for cancer therapies.

Original languageEnglish (US)
Pages (from-to)1687-1698
Number of pages12
JournalMolecular Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Aug 1 2019

Bibliographical note

Funding Information:
This work is supported by grants from the NIH to N. Shima primarily by NCI R03 CA227215 and partially by NIEHS R21 ES027062. We thank Drs. Eric Hendrickson and Alex Sobeck at the University of Minnesota for HCT116 cell lines. We also appreciate Madison Duffy, Anika Tella, and Madeleine Hinojos for their technical help. This work was supported in part by NIH P30 CA77598 utilizing the following: Masonic Cancer Center, University of Minnesota Shared Resource, Genome Engineering Shared Resource (GESR).

Funding Information:
This work is supported by grants from the NIH to N. Shima primarily by NCI R03 CA227215 and partially by NIEHS R21 ES027062. We thank Drs. Eric Hendrickson and Alex Sobeck at the University of Minnesota for HCT116 cell lines. We also appreciate Madison Duffy, Anika Tella, and Madeleine Hinojos for their technical help. This work was supported in part by NIH P30 CA77598

Publisher Copyright:
© 2019 American Association for Cancer Research.

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