FANCI functions as a repair/apoptosis switch in response to DNA crosslinks

Area of Science:

• Cellular biology
• Molecular biology
• DNA damage response

Background:

• Cells possess mechanisms to address DNA damage, either through repair or programmed cell death (apoptosis).
• The precise molecular switch governing this decision, particularly in response to interstrand crosslinks (ICLs), has been unclear.
• The FANCI/FANCD2 complex is known to initiate ICL repair.

Purpose of the Study:

• To elucidate the mechanism by which cells decide between DNA repair and apoptosis following ICL damage.
• To identify the key regulators involved in this critical cellular decision-making process.

Main Methods:

• Investigated protein-protein interactions of FANCI under various DNA damage conditions.
• Utilized genetic manipulations to alter ICL levels, endonuclease activity, and cell cycle progression.
• Examined the role of FANCI ubiquitination at K523 in regulating interactor selection.

Main Results:

• FANCI acts as a central switch, interacting with FANCD2 for repair or PIDD1 to initiate apoptosis via PIDDosome formation.
• This switch is triggered by ICL-repair failure, increased ICLs, or entry into mitosis.
• FANCI can dynamically switch back from PIDD1 to FANCD2 if PIDDosome assembly fails, indicating a bidirectional process.
• FANCI ubiquitination status at K523 influences its choice of interaction partners.

Conclusions:

• A novel repair-or-apoptosis switch regulated by FANCI has been identified in eukaryotic cells.
• This bidirectional switch ensures the elimination of severely damaged genomes while allowing cells to attempt repair if apoptotic pathways are initially defective.