biostudies-literatureCanesin GNational Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSNational Cancer InstituteNCI NIH HHS1801https://www.ebi.ac.uk/biostudies/studies/S-EPMC8307061biostudies-literatureUnknown10(7)Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed cells as well as lysis of red blood cells (RBC) (hemolysis). Labile heme originating from hemolysis acts as a DAMP while its breakdown products exert varying immunomodulatory effects. Labile heme is scavenged by hemopexin (Hx) and processed by heme oxygenase-1 (HO-1, <i>Hmox1</i>), resulting in its removal and the generation of biliverdin/bilirubin, carbon monoxide (CO) and iron. We recently demonstrated that labile heme accumulates in cancer cell nuclei in the tumor parenchyma of <i>Hx</i> knockout mice and contributes to the malignant phenotype of prostate cancer (PCa) cells and increased metastases. Additionally, this work identified Hx as a tumor suppressor gene. Direct interaction of heme with DNA G-quadruplexes (G4) leads to altered gene expression in cancer cells that regulate transcription, recombination and replication. Here, we provide new data supporting the nuclear role of HO-1 and heme in modulating DNA damage response, G4 stability and cancer growth. Finally, we discuss an alternative role of labile heme as a nuclear danger signal (NDS) that regulates gene expression and nuclear HO-1 regulated DNA damage responses stimulated by its interaction with G4.CellsHO-1 and Heme: G-Quadruplex Interaction Choreograph DNA Damage Responses and Cancer Growth.PMC8307061DK104714CA169904R01 DK125846R21 CA169904DK125846R21 CA256720CA256720R01 DK104714Swanson KDMuralidharan AMWegiel BCanesin GfalseHO-1 and Heme: G-Quadruplex Interaction Choreograph DNA Damage Responses and Cancer Growth.Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed cells as well as lysis of red blood cells (RBC) (hemolysis). Labile heme originating from hemolysis acts as a DAMP while its breakdown products exert varying immunomodulatory effects. Labile heme is scavenged by hemopexin (Hx) and processed by heme oxygenase-1 (HO-1, <i>Hmox1</i>), resulting in its removal and the generation of biliverdin/bilirubin, carbon monoxide (CO) and iron. We recently demonstrated that labile heme accumulates in cancer cell nuclei in the tumor parenchyma of <i>Hx</i> knockout mice and contributes to the malignant phenotype of prostate cancer (PCa) cells and increased metastases. Additionally, this work identified Hx as a tumor suppressor gene. Direct interaction of heme with DNA G-quadruplexes (G4) leads to altered gene expression in cancer cells that regulate transcription, recombination and replication. Here, we provide new data supporting the nuclear role of HO-1 and heme in modulating DNA damage response, G4 stability and cancer growth. Finally, we discuss an alternative role of labile heme as a nuclear danger signal (NDS) that regulates gene expression and nuclear HO-1 regulated DNA damage responses stimulated by its interaction with G4.2021-01-01T00:00:00Z2021 Jul2026-05-05T03:18:01.253Z2022-02-11T05:39:43.109ZS-EPMC83070613435997010.3390/cells10071801