DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway

Abstract

Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions. The multi-protein network is tightly regulated by complex mechanisms, such as ubiquitination, phosphorylation, and degradation signals that are critical for the maintenance of genome integrity and suppressing tumorigenesis. Here, we discuss recent advances in our understanding of how the FA proteins participate in ICL repair and regulation of the FA signaling network that assures the safeguard of the genome. We further discuss the potential application of designing small molecule inhibitors that inhibit the FA pathway and are synthetic lethal with DNA repair enzymes that can be used for cancer therapeutics.

New paradigm of functional regulation by DNA mimic proteins: Recent updates

“…Using the structure of the SAUGI/human UDG complex to explain the conserved binding strategy of SAUGI to UDGs. (Left) The UDG component of the human UDG/ DNA complex showing four functional motifs of human UDG: Water‐activating loop: 63‐QDPYH‐67 (blue), Pro‐rich loop: 165‐PPPPS‐169 (green), Gly‐Ser loop: 246‐GS‐247 (red), and Minor groove intercalation loop: 268‐HPSPLS‐273 (yellow). These motifs play important roles in the DNA substrate binding and glycosidase activity of UDGs .…”

CTCF regulates the FoxO signaling pathway to affect the progression of prostate cancer

“…[34][35][36] Research has shown that the inactivation of AKT results in dephosphorylation and activation of FOXO transcription factors, which is involved in mediating cell cycle arrest, DNA repair and apoptosis. The therapy approach of targeting CTCF seems to be promising for the treatment of PC by regulating the FoxO signalling pathway and further retarding cancer progression.…”

“…Additionally, there have been an increasing number of studies on the use of combination therapies to treat cancer using DNA repair mechanisms. [34][35][36] Research has shown that the inactivation of AKT results in dephosphorylation and activation of FOXO transcription factors, which is involved in mediating cell cycle arrest, DNA repair and apoptosis. 31,32 It would be feasible to make a combination therapy via DNA repair progression.…”

RecGwed: A probable novel regulator in the resolution of branched DNA structures in mycobacteria

“…AP sites and cross‐linked bases are usually repaired by BER, NER and MMR pathways during pre‐replicative stages . In post‐replicative stages of cell cycle, recombination machinery plays a critical role in DNA repair and replication restart . The up‐regulation of recG wed in M. smegmatis during stationary phase/UV damage, and down‐regulation during H 2 O 2 /MMS stress, indicates that the protein may play an active role in post‐replicative (stationary phase) recombination events, that proceed though branched DNA intermediates.…”