{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:18:29Z","timestamp":1791299909014,"version":"4.1.0"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":61,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,2]]},"abstract":"<jats:p>\n                    Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by\n                    <jats:italic>CCND1<\/jats:italic>\n                    ) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS and DSB repair mechanisms. Cyclin D1 overexpression elevated RS, increased DNA damage, especially during mitosis, and caused specific upregulation of MMEJ. Furthermore, cyclin D1 activated polymerase theta (\n                    <jats:italic>POLQ<\/jats:italic>\n                    ) transcription by binding its promoter loci, driving POL\u0398-mediated MMEJ that is essential to withstand cyclin D1\u2013induced RS. Moreover, concurrent ATM deficiency further intensified RS, enhanced\n                    <jats:italic>POLQ<\/jats:italic>\n                    expression, and heightened reliance on MMEJ-mediated DNA damage repair. Consequently, inhibition of POL\u0398 in cyclin D1\u2013overexpressed settings further exacerbated RS, causing single-strand DNA gap accumulations and chromosomal instability, ultimately leading to apoptosis, an effect amplified in ATM-deficient cells. Targeting MMEJ via POL\u0398 inhibition is therefore an effective strategy in the context of cyclin D1 overexpression and ATM deficiency and may provide a unique therapeutic approach for treating MCL and other malignancies characterized by similar alterations.\n                  <\/jats:p>","DOI":"10.1172\/jci193006","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T12:00:47Z","timestamp":1751544047000},"source":"Crossref","is-referenced-by-count":13,"title":["Cyclin D1 overexpression induces replication stress and microhomology-mediated end-joining dependence in mantle cell lymphoma"],"prefix":"10.1172","volume":"135","author":[{"given":"Jithma P.","family":"Abeykoon","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA."},{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Asada","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuna","family":"Hirohashi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Moreau","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Bayer Pharmaceuticals, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirisha","family":"Mukkavalli","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalindi","family":"Parmar","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Zambrano","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lige","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA."},{"name":"Dr. Kiran C. 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