DNA damage-binding protein explained

damage-specific DNA binding protein 1, 127kDa
Hgncid:2717
Symbol:DDB1
Altsymbols:XPE
Entrezgene:1642
Omim:600045
Refseq:NM_001923
Uniprot:Q16531
Chromosome:11
Arm:q
Band:12
Locussupplementarydata:-q13
damage-specific DNA binding protein 2, 48kDa
Hgncid:2718
Symbol:DDB2
Altsymbols:DBB, UV-DDB2, FLJ34321
Entrezgene:1643
Omim:600811
Refseq:NM_000107
Uniprot:Q92466
Chromosome:11
Arm:p
Band:12
Locussupplementarydata:-p11

DNA damage-binding protein or UV-DDB is a protein complex that is responsible for repair of UV-damaged DNA. This complex is composed of two protein subunits, a large subunit DDB1 (p127) and a small subunit DDB2 (p48). When cells are exposed to UV radiation, DDB1 moves from the cytosol to the nucleus and binds to DDB2, thus forming the UV-DDB complex. This complex formation is highly favorable and it is demonstrated by UV-DDB's binding preference and high affinity to the UV lesions in the DNA.[1] This complex functions in nucleotide excision repair, recognising UV-induced (6-4) pyrimidine-pyrimidone photoproducts and cyclobutane pyrimidine dimers.

Structure

The helical domain at the n-terminus of DDB2 binds to UV damaged DNA with high affinity to form the UV-DDB complex. The helical binding interaction at the n-terminus of DDB2 allows for the protein to bind immediately after detecting UV damaged DNA. DNA binds to DDB2 only when damaged by UV radiation. Binding with high affinity to a helical domain of DDB2 in the dimer form, UV-DDB, is facilitated by the n-terminal alpha helical paddle and beta wings of the DDB2 subunit. Both the alpha helical fold and the beta wing loops form a "winged helix" motif. The dimerized complex acts as a scaffold for DNA damage repair pathways and allows for other proteins to detect, interact, and repair UV damaged DNA.

DDB2

DDB2 is a protein part of the CUL4A–RING ubiquitin ligase (CRL4) complex. It was thought that DDB2 only acts to recognize legions of UV damaged DNA. It has been found that DDB2 plays a role in promoting chromatin unfolding.[2] This role is independent of DDB2's role in the CRL4 complex.

Damage sensor role

UV-DDB is not only responsible for the repair of damaged DNA, it can also function by acting as a damage sensor.[3] In base excision repair, UV-DDB galvanizes OGG1 and APE 1 activities. During DNA damage, proteins OGG1 and APE 1 encounter difficulty in repairing the lesions in a DNA wrapped nucleosome. Additionally, histones function by making the DNA inaccessible because of the way they make DNA coil and wrap into chromatin. UV-DDP plays a role in identifying the damaged sites within the chromatin, thereby allowing access to base excision repair proteins. When UV-DDB is recruited to these damaged sites, it recognizes the OGG1- AP DNA complex and further accelerates the turnover of glycosylases.

Notes and References

  1. Yeh JI, Levine AS, Du S, Chinte U, Ghodke H, Wang H, Shi H, Hsieh CL, Conway JF, Van Houten B, Rapić-Otrin V . 6 . Damaged DNA induced UV-damaged DNA-binding protein (UV-DDB) dimerization and its roles in chromatinized DNA repair . Proceedings of the National Academy of Sciences of the United States of America . 109 . 41 . E2737-46 . October 2012 . 22822215 . 10.1073/pnas.1110067109 . 3478663 . free .
  2. Luijsterburg MS, Lindh M, Acs K, Vrouwe MG, Pines A, van Attikum H, Mullenders LH, Dantuma NP . 6 . DDB2 promotes chromatin decondensation at UV-induced DNA damage . The Journal of Cell Biology . 197 . 2 . 267–81 . April 2012 . 22492724 . 10.1083/jcb.201106074 . 3328393 . free .
  3. Jang S, Kumar N, Beckwitt EC, Kong M, Fouquerel E, Rapić-Otrin V, Prasad R, Watkins SC, Khuu C, Majumdar C, David SS, Wilson SH, Bruchez MP, Opresko PL, Van Houten B . 6 . Damage sensor role of UV-DDB during base excision repair . Nature Structural & Molecular Biology . 26 . 8 . 695–703 . August 2019 . 31332353 . 10.1038/s41594-019-0261-7 . 6684372 .