CARELL GROUP Research – DNA Repair

The Carell group developed phosphoramidite reagents and solid-phase synthesis protocols to incorporate a large number of partially highly sensitive DNA lesions into DNA oligonucleotides (Fig. 1).

Figure 1: DNA lesion that were synthesized and incorporated into oligonucleotides by the Carell group.

These synthetic achievements allowed us to crystallize these lesion-containing oligonucleotides together with DNA repair enzymes and proteins that recognize and repair these lesions in the genome in order to counteract the harmful effects of lesions in the genome. These crystal structures (Fig. 2) provided deep insight into the molecular mechanisms associated with lesion recognition and repair. A dinucleotide flip-out mechanism was discovered for the repair of UV-lesions by photolyases and new electron transfer reactions were discovered that lead to the repair of UV-induced lesions.

Lesions containing DNA were also crystallized together with different DNA polymerases, which taught us how these lesions induce mutations when repair is not complete.

Figure 2: Selected crystal structures of lesion containing DNA with proteins. The structures from left to right. Top: DNA polymerase with 8oxodG-DNA (with L. Beese), Polymerase eta with cisplatin-DNA, RNA-Pol II with cisplatin-DNA (with P. Cramer). Bottom: CPD photolyase with CPD lesion-DNA (with L.-O. Essen), (6-4) photolyase with 6-4 lesion-DNA (with I. Schlichting) Rad14/XPA with AAF-dG-DNA (with C. Kisker).