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Upcoming Seminars

Francesca Carlomagno, MD, PhD - "Links Between Cell Cycle Control and Iron Metabolism"

Full Professor, IEOS c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita' degli Studi di Napoli Federico II
When Oct 08, 2019
from 12:00 PM to 01:00 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Abstract
Iron is crucial for many enzymes involved in DNA replication and for dNTPs synthesis. Indeed, limited iron availability affects cell proliferation inducing G1 arrest in order to avoid replication stress and DNA damage. NCOA4 is an iron-sensing protein that is stabilized in low iron conditions to promote ferritin degradation. Interestingly, NCOA4 exerts also a negative control on DNA replication origin activation in iron deficiency conditions in order to maintain genome stability. Thus, in DFO treated cells we observed increased binding of NCOA4 to MCM2-7 and to chromatin, and in particular to canonical DNA replication origins.  Indeed, in low iron conditions NCOA4-depleted HeLa cells (shNCOA4) activated more DNA replication origins than control cells showing reduced inter-origin distance and decreased fork rate with signs of replication stress.  Unscheduled DNA replication with associated signs of replication stress observed in HeLa-shNCOA4 cells lead to activation of a DNA Damage Response with phosphorylation of ATR, CHK1 and gamma-H2AX, permanent cell cycle arrest and reduced cell survival. Consistently, NCOA4 null mice displayed a decreased tolerance to tissue insults such as Dextran Sulfate-induced acute colitis with decreased proliferating crypts (eg pH3 positive cells) and increased DNA damage (eg pCHK2 positive cells) and apoptotic cells (eg Caspase 3 positive cells), reflecting an overall impairment of intestinal cell renewal. Collectively, our data describe a new cellular response activated in iron deficiency that exploit NCOA4 protein as a cell proliferation brake, to align DNA replication origin activation and iron fluctuations in order to avoid DNA replication stress.