Abstract
Background Eschericia coli AlkB is a 2-oxoglutarate- and iron-dependent dioxygenase that reverses alkylated DNA damage by oxidative demethylation. Mouse AlkB homolog 1 (Alkbh1) is one of eight members of the newly discovered family of mammalian dioxygenases.Methods and FindingsIn the present study we show non-Mendelian inheritance of the Alkbh1 targeted allele in mice. Both Alkbh1−/− and heterozygous Alkbh1+/− offspring are born at a greatly reduced frequency. Additionally, the sex-ratio is considerably skewed against female offspring, with one female born for every three to four males. Most mechanisms that cause segregation distortion, act in the male gametes and affect male fertility. The skewing of the sexes appears to be of paternal origin, and might be set in the pachythene stage of meiosis during spermatogenesis, in which Alkbh1 is upregulated more than 10-fold. In testes, apoptotic spermatids were revealed in 5–10% of the tubules in Alkbh1−/− adults. The deficiency of Alkbh1 also causes misexpression of Bmp2, 4 and 7 at E11.5 during embryonic development. This is consistent with the incompletely penetrant phenotypes observed, particularly recurrent unilateral eye defects and craniofacial malformations.ConclusionsGenetic and phenotypic assessment suggests that Alkbh1 mediates gene regulation in spermatogenesis, and that Alkbh1 is essential for normal sex-ratio distribution and embryonic development in mice.
Highlights
The Eschericia coli (E. coli) DNA repair enzyme AlkB demethylates e.g. 1-methyladenine (1-meA) to adenine – generating succinate and formaldehyde – in the presence of iron as cofactor and 2oxoglutarate as cosubstrate [1,2]
Genetic and phenotypic assessment suggests that AlkB homolog 1 (Alkbh1) mediates gene regulation in spermatogenesis, and that Alkbh1 is essential for normal sex-ratio distribution and embryonic development in mice
We demonstrate that Alkbh1 deficiency in mice results in apoptosis in adult testes and sex-ratio distortion of offspring, most likely caused by defects in the pachytene stage during spermatogenesis
Summary
The Eschericia coli (E. coli) DNA repair enzyme AlkB demethylates e.g. 1-methyladenine (1-meA) to adenine – generating succinate and formaldehyde – in the presence of iron as cofactor and 2oxoglutarate as cosubstrate [1,2]. Except for Alkbh, all the remaining proteins have been identified throughout the animal kingdom, suggesting fundamental roles in biological processes [4]. Two of these homologs, ALKBH2 and ALKBH3 in humans (Alkbh and Alkbh in mice), are similar to E. coli AlkB in that they efficiently repair damaged nucleic acids in the presence of iron and 2-oxoglutarate in vitro [5,6,7,8,9]. Alkbh is the major, probably only, dioxygenase that repairs 1-meA DNA in vivo and mice lacking Alkbh accumulate 1-meA in the genome during ageing [10]. Mouse AlkB homolog 1 (Alkbh1) is one of eight members of the newly discovered family of mammalian dioxygenases
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