Results: 5

1.
Figure 1

Figure 1. DNA adducts formed by interstrand crosslinking agents. From: Fanconi Anemia Proteins and Endogenous Stresses.

Bifunctional compounds can form monoadducts that affect a single nucleotide. Or these compounds can form adducts affect two nucleotides in the same strand or two paired strands to generate DNA intrastrand and interstrand crosslinks, respectively.

Qishen Pang, et al. Mutat Res. ;668(1-2):42-53.
2.
Figure 5

Figure 5. Schematic diagram of possible roles of FANCD2 at replication forks. From: Fanconi Anemia Proteins and Endogenous Stresses.

FANCD2, and perhaps other FA proteins, could have a role in restarting stalled replication forks, as symbolized here by the re-engagement of DNA polymerases at the replication fork. FA proteins could also have a role in preventing the collapse of stalled replication forks, as symbolized here, by stabilizing the association of DNA polymerases with the replication fork. FA proteins may have roles in the intra-S phase checkpoint, which primarily blocks new initiation of replication following DNA damage. Finally, FANCD2 and other FA proteins may simply be recruited to repair DNA damage encountered by the replication fork.

Qishen Pang, et al. Mutat Res. ;668(1-2):42-53.
3.
Figure 2

Figure 2. Outline of potential sources of endogenous DNA damage that could activate the FA-BRCA pathway. From: Fanconi Anemia Proteins and Endogenous Stresses.

(A) Reactive oxygen species (ROS) can induce lipid peroxidation, which can generate bifunctional compounds that induce ICLs in DNA. (B) ROS can directly oxidize bases in DNA. (C) Telomere dysfunction, through disruption of telomere packaging or through shortening of telomeres to a critical length, can lead to recruitment of DNA damage response proteins (DDR) to telomeres. (D) Endogenous DNA damage, replication errors, or chromatin structures that are difficult to replicate, can induce replication stress and/or fork collapse.

Qishen Pang, et al. Mutat Res. ;668(1-2):42-53.
4.
Figure 3

Figure 3. Major organelles and enzymes known to generate ROS. From: Fanconi Anemia Proteins and Endogenous Stresses.

The activity of the respiratory chain in the mitochondria is responsible for most ROS produced in aerobiosis. On the other hand, the metabolic pathway that drives the degradation of long chain fatty acids in the peroxisome is also an important ROS source. The activity of ROS produced by cytochrome p450 or NADPH oxidases may be restricted to the area where they are located, and not all ROS are sufficiently stable to traverse a cell and damage DNA in the nucleus. 5-lipoxygenase can be found associated with membranes or with the nuclear envelope. Peroxisomal xanthine oxidase is an enzyme that produces ROS from molecular oxygen.

Qishen Pang, et al. Mutat Res. ;668(1-2):42-53.
5.
Figure 4

Figure 4. Schematic of the ATR-Chk1 pathway and possible targets for phosphorylation in the FA pathway. From: Fanconi Anemia Proteins and Endogenous Stresses.

RAD17 functions as a clamp loader for the RAD9-RAD1-HUS1 trimer. This trimer acts as a ring that can slide on DNA to act as a sensor of DNA damage, and activates ATR in response to replication stress or blockage of replication forks by DNA damage. RPA is a single-strand DNA binding protein that independently recruits the ATRIP-ATR complex through direct binding of RPA to ATRIP. ATR then activates the downstream Chk1 kinase by phosphorylating it. Claspin also forms a ring-like structure that can slide on DNA and which is required for phosphorylation of Chk1 by ATR. ATR also phosphorylates a large number of other DNA damage response proteins, including RAD17 and RAD9. (B) ATR or Chk1-dependent phosphorylation of multiple FA proteins, including FANCA, FANCE, FANCDD2, and FANCDI, may regulate their recruitment to sites of replication stress. Phosphorylation of FANCA, FANCI, and FANCD2 by ATR ultimately upregulates monoubiquitination of FANCD2 and FANCI in response to replication stress or DNA damage. The stability of FANCE, a member of the FA nuclear core complex, is regulated by Chk1-mediated phosphorylation.

Qishen Pang, et al. Mutat Res. ;668(1-2):42-53.

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