Angiopoietin-like protein 8 directs DNA damage responses towards apoptosis by stabilizing PARP1-DNA condensates

Area of Science:

• Cellular biology
• Molecular biology
• Genetics

Background:

• Cells utilize DNA damage responses (DDRs) like repair or apoptosis to maintain genome integrity under genotoxic stress.
• The molecular mechanisms determining the choice between DNA repair and apoptosis remain largely unknown.

Purpose of the Study:

• To identify novel regulators that dictate the cellular decision between DNA repair and apoptosis following genotoxic insult.
• To elucidate the role of angiopoietin-like protein 8 (ANGPTL8) in modulating DNA damage responses.

Main Methods:

• Investigated the subcellular localization and function of ANGPTL8 in response to genotoxic stress.
• Utilized cell culture models and mouse models of liver ischemia/reperfusion and cisplatin treatment.
• Performed co-immunoprecipitation to study protein interactions and analyzed PARP1-DNA condensate dynamics.

Main Results:

• ANGPTL8 localizes to the nucleus and functions as a switch, promoting apoptosis over DNA repair after genotoxin exposure.
• ANGPTL8 deficiency reduced DNA damage and apoptosis in vitro and in vivo.
• ANGPTL8 interacts with Poly (ADP-ribose) polymerase 1 (PARP1), decreasing condensate fluidity and enhancing pro-apoptotic PARP1 accumulation.
• ANGPTL8 transcription is downregulated by CCAAT enhancer binding protein alpha (CEBPA) under genotoxic stress.

Conclusions:

• ANGPTL8 is a novel nuclear regulator that channels genotoxic stress-induced DNA damage responses towards apoptosis.
• Understanding ANGPTL8's role provides insights into safeguarding genome integrity through programmed cell death.