Poly ADPRibose Polymerase 1231 PARP Structure and Function

Sperm DNA integrity is critical for successful embryo development and the transmission of intact genetic material to the offspring [2]. During spermatogenesis, protection of the sperm DNA is achieved by tight packaging into a condensed chromatin. Incomplete chromatin condensation and persistence of DNA strand breaks during spermatogenesis are associated with DNA damage and male infertility [65], PARP, a DNA damage repair enzyme, has been first introduced by Chambon et al. in 1963. It is associated with chromatin and specifically found in the nucleolus [66]. To date, 18 different PARP homologues have been identified, but the structure and function of some are not known yet [67]. Each PARP family member has a catalytic part which contains 50 amino acids that act as the "PARP signature" [67]. PARP family members have other domains, such as DNA-binding domains (DBDs), ankyrin repeats, WWEs domain, macro domains, and BRCA-1 domain with C terminus which is activated following DNA damage [68]. PARP proteins detect DNA strand breaks and have a particular role in both the base excision repair (BER) and nucleotide repair pathways [69]. They have been shown in testicular germ cells [69, 70],

Members of the PARP family have been categorized according to the functional domain. The first category includes PARP1 and PARP2 is activated in response to DNA strands break. Tankyrases 1 and 2 are in second group and have different functions such as telomere regulation and mitotic segregation. The third group consists of PARP12, PARP13, and TCDD-inducible PARP, which contain CCCH-type zinc fingers. Finally, the fourth group includes PARP9, PARP14, and PARP15 which have 1-3 macro domains connected to a PARP domain. They have WWE domain and a catalytic function. For other PARPs such as PARP8, 11, 16, and PARP6, no domains have been found, except a WWE domain in PARP11, therefore it is difficult to define any possible functional role for them [71].

PARP family members were recently classified on the basis of their catalytic domain sequences by Hassa and Hottiger [72]. They were divided into three groups: group 1 including PARP1, PARPb (short PARP1), PARP2, and PARP3; group 2 consists of PARP4; and group 3 consists of two PARP members, tankyrase-1, tankyrase

ADPR

ADPR ADPR ADPR

ADPR ADPR

DNA binding domain

(1-373 amino acids)

Site of Cleavage

Automodification domain

(374-533 amino acids)

Catalytic domain (534-1014 amino acids)

Full length PARP (113 kDa)

Short fragment (24 kDa)

Long fragment (89 kDa)

Cleaved PARP Fragments

Fig. 12.1 Structural domains of PARP and its fragments. (a) DNA-binding domain containing Zinc fingers (F1-3) for nucleosome binding and nuclear localization (NLS) segment; Automodification domain responsible for adding ADPR (ADP-ribose) polymers through binding with Lysine (K) amino acid and catalytic domain has the PARP signature and PARP enzymatic activity. (b) Full-length PARP1 113 kDa molecule with a mark on the site of cleavage (214/215 amino acids). (c) PARP cleavage by caspase showing short (24 kDa) and long (89 kDa) cleaved PARP fragments [2]

2a, and its isoform tankyrase-2b, known as PARP5 and PARP6a/b [72]. The prototype enzyme of the PARP family is PARP1, a 113 kDa enzyme encoded by the ADP-ribosyl transferase (ADPRT) gene that sited on chromosome 1 in humans [67],

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